猪流感病毒感染细胞内p53活性变化机制解析
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摘要
肿瘤抑制因子p53在细胞中具有细胞周期捕获、诱导细胞凋亡和抗病毒等功能。流感病毒感染细胞后,诱导被感染细胞发生凋亡,胞内的p53分子蛋白水平和活性呈现双相性上升的变化,这种变化是与病毒的复制密切相关。
本研究首先探讨猪流感病毒感染细胞后p53分子活性的变化机制。由于前人研究结果表明p53蛋白水平的增加和活化与其翻译后修饰有关,而与转录水平没有关系。本试验利用Real-time PCR和半定量PCR分别检测病毒感染MDCK细胞p53分子mRNA水平,结果表明猪流感病毒感染并没有使p53转录水平发生改变。利用蛋白质合成抑制剂放线菌酮处理猪流感病毒感染的Vero和MDCK细胞,Western-blotting检测p53分子稳定性的变化,结果表明病毒感染组p53稳定性比未感染组明显上升,证实病毒感染细胞p53蛋白水平的增加是由于其稳定性增加造成的。利用蛋白酶体抑制剂MG132处理流感病毒感染的Vero细胞,结合使用放线菌酮,Western-bloting检测p53分子蛋白水平的变化,结果表明感染组和未感染组在降解途径受到抑制时p53稳定性没有明显差异,所以流感病毒感染使p53分子稳定性增加是与蛋白酶体降解途径密切相关。p53分子需要泛素化标签才能通过蛋白酶体途径进行降解,本试验利用蛋白酶体抑制剂MG132处理流感病毒感染的CV1和Vero细胞,检测泛素化p53的水平,结果表明病毒感染细胞组p53泛素化水平明显比未感染组少,说明流感病毒感染明显减少p53泛素化水平。
前人研究表明参与p53泛素化的主要酶是Mdm2分子,本试验利用Mdm2抑制剂处理病毒感染的细胞,Western-bloting检测发现在病毒组和未感染组泛素化p53几乎检测不到,所以说明流感病毒感染引起p53泛素化水平减少是通过Mdm2介导途径来完成的。本试验利用Western-bloting检测猪流感病毒感染后Mdm2分子蛋白水平的变化,间接免疫荧光检测Mdm2亚细胞定位变化,结果表明流感病毒感染的细胞Mdm2蛋白水平没有发生明显变化,且其亚细胞定位也没有发生改变。p53蛋白的降解需要其多泛素化标签,p53多泛素化连接酶是p300,本试验检测了流感病毒感染MDCK细胞后p300的蛋白水平,发现p300的蛋白水平随着病毒的复制而增加,证明多泛素化p53的减少不是由于p300的表达量引起的。
Mdm2与p53发生相互绑定是p53泛素化的必要条件,本试验利用H1299细胞转染外源性GFP-p53,感染流感病毒24h后Co-IP检测Mdm2与p53亲和能力,另外在病毒感染CV1细胞20 h后,Co-IP检测Mdm2与p53亲和能力,结果表明流感病毒感染明显减弱了Mdm2与p53之间的相互作用。前人研究表明Thr18的磷酸化是p53和Mdm2相互作用下降的机制之一,本试验检测了流感病毒感染后p53蛋白392位Ser和18位Thr的磷酸化水平,结果表明这两个位点磷酸化都明显升高,推测流感病毒感染造成p53磷酸化水平升高是导致p53和Mdm2相互作用下降的机制之一。
流感病毒复制时其病毒蛋白在抵抗宿主抗病毒效应中发挥重要的功能,特别是其非结构蛋白NS1在胞内各种信号通路中都发挥重要的功能。在Vero细胞中共转染流感病毒各基因真核表达质粒和双报告基因质粒,测定p53相对luciferase活性,结果表明NS1能显著地抑制p53的活性,NP能显著激活p53活性。Western-blotting和间接免疫荧光试验结果表明NS1、NP既不影响p53的蛋白水平又不影响p53的亚细胞定位。NS1和p53共转染H1299细胞,流式细胞术和TUNNEL试剂盒检测细胞凋亡,结果表明NS1能显著抑制p53介导的细胞凋亡。利用PCR定点诱变技术构建不同的NS1突变体,不同突变体与p53-luc双报告基因质粒共转染Vero细胞,测定p53相对luciferase活性,结果表明NS1蛋白的144-188位氨基酸是决定NS1抑制p53活性的关键位点,且flag-NS1-△144/188不能抑制p53介导的细胞凋亡。Flag-NS1-wt及flag-NS1-△144/188和GFP-p53共转染H1299细胞,Co-IP实验结果表明NS1能绑定p53,而flag-NS1-△144/188突变体也能绑定p53,所以这种绑定可能是NS1抑制p53活性的机制之一。
另外也筛选到能显著激活p53活性的流感病毒蛋白NP,初步筛选到与激活p53活性相关的位点为NP的C端结构域,但是NP与p53介导的细胞凋亡没有关系,NP激活p53的详细机制和生物学意义需要进一步进行研究。
总之,本研究解析了流感病毒感染细胞p53活性变化机制,以及病毒蛋白参与p53活性调节的机制。该机制可能是流感病毒逃逸宿主先天性免疫的方法之一,它为以后研究流感病毒抗病毒药物的开发提供理论基础,也为流感病毒与宿主细胞之间相互作用提供研究模型。
Tumor suppressor p53 plays an important role in mediating apoptosis and cell cycle capture in response to different stress including virus infection, and regulating host antiviral defense is new function of p53. Influenza A virus (IAV) induces apoptosis of infected cells, p53 is accumulated and activated in IAV infected cells, the results showed biphagic patterns of p53 accumulation and activity, which is associated with IAV replication.
This study was undertaken to examine the mechanism of p53 accumulation and activity in IAV-infected cells. Here we show that p53 accumulation in IAV-infected cells resulted from protein stabilization, which was associated with a weakened p53-Mdm2 interaction. In IAV-infected cells, p53 was stabilized and its half-life was remarkably extended. The ladders of poly-ubiquitinated p53 were not detectable in the presence of proteasome inhibitor MG132 and less sensitive to proteasome-mediated degradation during IAV-infection.
In the infected cells where Mdm2 is responsible for regulating p53 mono-ubiquitination, neither a lack of abundance nor altered sub-cellular distribution of Mdm2 was observed, furthermore, poly-ubiquitination ligase p300 expressed in a higher level than uninfected cells. However, a weakened p53-Mdm2 interaction was detected by co-immunoprecipitation. In addition, an increase in phosphorylation of p53 at Thr18 and Ser392 was observed. We propose that the mechanism underlying the increased p53 stabilization is that IAV infection induced a weakened p53-Mdm2 interaction, which led to a decrease in ubiquitination levels of p53, consequently resulting in the increased p53 stabilization. The increase in phosphorylation of p53 at Thr18 presumably contributed to the weakened p53-Mdm2 interaction.
Viral proteins play important roles in resistance to host anti-viral effects, especially its non-structural protein NS1 have played a variety of important functions during the intracellular signaling pathway. In interferon deficient Vero cells, p53 luciferase activities were detected by co-transfection experiments and dual reporter genes system. The results showed that NS1 inhibits the activity of p53 remarkably. However, NS1 does not affect the p53 protein levels and subcellular localization as detected by western-blotting and indirect immunofluorescence assay. NS1 and p53 were co-transfected into H1299 cells, apoptosis were detected by flow cytometry and apoptosis detection kit TUNNEL. The results showed that NS significantly inhibits p53-mediated apoptosis. To construct different deletion mutants of NS1, modified PCR-based site-directed mutagenesis was performed. To screen domain responsible for inhibiting p53 activity, p53 luciferase activity were detected by dual reporter gene systems. The results showed that the 144-188 amino acid of NS1 protein is a key domain responsible for inhibiting p53 activity. The flag-NS1-△144/188 did not inhibit p53 activity. Furthermore, the flag-NS1-△144/188 was unable to inhibit p53-mediated apoptosis. H1299 cells were co-transfected with GFP-p53 and Flag-NS1-wt or flag-NS1-△144/188 respectively. The results showed that NS1 associates with p53, and flag-NS1-△144/188 mutant was also able to bind p53 as detected by Co-IP experiment. So NS1 bound to p53 was one of mechanisms underlying the inhibition of p53 activity, the 144-188 domain of NS1 protein is an inhibitory domain but not a binding domain.
In addition, viral protein NP was found to activate p53 activity, but did not activate p53 mediated apoptosis. It regulated the activity of p53 by competing with the NS1. The domain responsible for activating p53 was located at the C-terminal of NP. The detailed mechanism and the biological significance of activation p53 by NP need uncover in the future.
Finally,this study analysis the mechanism of dynamics of p53 activity in influenza virus infected cells, the virus proteins involved in regulating p53 activity. This may be one of the mechanisms that influenza viruses escaped host innate immune. Those researches provided theoretical basis for study of anti-influenza virus drug develop- ment and model for influenza virus and host-cells interaction researches in the future.
本研究首先探讨猪流感病毒感染细胞后p53分子活性的变化机制。由于前人研究结果表明p53蛋白水平的增加和活化与其翻译后修饰有关,而与转录水平没有关系。本试验利用Real-time PCR和半定量PCR分别检测病毒感染MDCK细胞p53分子mRNA水平,结果表明猪流感病毒感染并没有使p53转录水平发生改变。利用蛋白质合成抑制剂放线菌酮处理猪流感病毒感染的Vero和MDCK细胞,Western-blotting检测p53分子稳定性的变化,结果表明病毒感染组p53稳定性比未感染组明显上升,证实病毒感染细胞p53蛋白水平的增加是由于其稳定性增加造成的。利用蛋白酶体抑制剂MG132处理流感病毒感染的Vero细胞,结合使用放线菌酮,Western-bloting检测p53分子蛋白水平的变化,结果表明感染组和未感染组在降解途径受到抑制时p53稳定性没有明显差异,所以流感病毒感染使p53分子稳定性增加是与蛋白酶体降解途径密切相关。p53分子需要泛素化标签才能通过蛋白酶体途径进行降解,本试验利用蛋白酶体抑制剂MG132处理流感病毒感染的CV1和Vero细胞,检测泛素化p53的水平,结果表明病毒感染细胞组p53泛素化水平明显比未感染组少,说明流感病毒感染明显减少p53泛素化水平。
前人研究表明参与p53泛素化的主要酶是Mdm2分子,本试验利用Mdm2抑制剂处理病毒感染的细胞,Western-bloting检测发现在病毒组和未感染组泛素化p53几乎检测不到,所以说明流感病毒感染引起p53泛素化水平减少是通过Mdm2介导途径来完成的。本试验利用Western-bloting检测猪流感病毒感染后Mdm2分子蛋白水平的变化,间接免疫荧光检测Mdm2亚细胞定位变化,结果表明流感病毒感染的细胞Mdm2蛋白水平没有发生明显变化,且其亚细胞定位也没有发生改变。p53蛋白的降解需要其多泛素化标签,p53多泛素化连接酶是p300,本试验检测了流感病毒感染MDCK细胞后p300的蛋白水平,发现p300的蛋白水平随着病毒的复制而增加,证明多泛素化p53的减少不是由于p300的表达量引起的。
Mdm2与p53发生相互绑定是p53泛素化的必要条件,本试验利用H1299细胞转染外源性GFP-p53,感染流感病毒24h后Co-IP检测Mdm2与p53亲和能力,另外在病毒感染CV1细胞20 h后,Co-IP检测Mdm2与p53亲和能力,结果表明流感病毒感染明显减弱了Mdm2与p53之间的相互作用。前人研究表明Thr18的磷酸化是p53和Mdm2相互作用下降的机制之一,本试验检测了流感病毒感染后p53蛋白392位Ser和18位Thr的磷酸化水平,结果表明这两个位点磷酸化都明显升高,推测流感病毒感染造成p53磷酸化水平升高是导致p53和Mdm2相互作用下降的机制之一。
流感病毒复制时其病毒蛋白在抵抗宿主抗病毒效应中发挥重要的功能,特别是其非结构蛋白NS1在胞内各种信号通路中都发挥重要的功能。在Vero细胞中共转染流感病毒各基因真核表达质粒和双报告基因质粒,测定p53相对luciferase活性,结果表明NS1能显著地抑制p53的活性,NP能显著激活p53活性。Western-blotting和间接免疫荧光试验结果表明NS1、NP既不影响p53的蛋白水平又不影响p53的亚细胞定位。NS1和p53共转染H1299细胞,流式细胞术和TUNNEL试剂盒检测细胞凋亡,结果表明NS1能显著抑制p53介导的细胞凋亡。利用PCR定点诱变技术构建不同的NS1突变体,不同突变体与p53-luc双报告基因质粒共转染Vero细胞,测定p53相对luciferase活性,结果表明NS1蛋白的144-188位氨基酸是决定NS1抑制p53活性的关键位点,且flag-NS1-△144/188不能抑制p53介导的细胞凋亡。Flag-NS1-wt及flag-NS1-△144/188和GFP-p53共转染H1299细胞,Co-IP实验结果表明NS1能绑定p53,而flag-NS1-△144/188突变体也能绑定p53,所以这种绑定可能是NS1抑制p53活性的机制之一。
另外也筛选到能显著激活p53活性的流感病毒蛋白NP,初步筛选到与激活p53活性相关的位点为NP的C端结构域,但是NP与p53介导的细胞凋亡没有关系,NP激活p53的详细机制和生物学意义需要进一步进行研究。
总之,本研究解析了流感病毒感染细胞p53活性变化机制,以及病毒蛋白参与p53活性调节的机制。该机制可能是流感病毒逃逸宿主先天性免疫的方法之一,它为以后研究流感病毒抗病毒药物的开发提供理论基础,也为流感病毒与宿主细胞之间相互作用提供研究模型。
Tumor suppressor p53 plays an important role in mediating apoptosis and cell cycle capture in response to different stress including virus infection, and regulating host antiviral defense is new function of p53. Influenza A virus (IAV) induces apoptosis of infected cells, p53 is accumulated and activated in IAV infected cells, the results showed biphagic patterns of p53 accumulation and activity, which is associated with IAV replication.
This study was undertaken to examine the mechanism of p53 accumulation and activity in IAV-infected cells. Here we show that p53 accumulation in IAV-infected cells resulted from protein stabilization, which was associated with a weakened p53-Mdm2 interaction. In IAV-infected cells, p53 was stabilized and its half-life was remarkably extended. The ladders of poly-ubiquitinated p53 were not detectable in the presence of proteasome inhibitor MG132 and less sensitive to proteasome-mediated degradation during IAV-infection.
In the infected cells where Mdm2 is responsible for regulating p53 mono-ubiquitination, neither a lack of abundance nor altered sub-cellular distribution of Mdm2 was observed, furthermore, poly-ubiquitination ligase p300 expressed in a higher level than uninfected cells. However, a weakened p53-Mdm2 interaction was detected by co-immunoprecipitation. In addition, an increase in phosphorylation of p53 at Thr18 and Ser392 was observed. We propose that the mechanism underlying the increased p53 stabilization is that IAV infection induced a weakened p53-Mdm2 interaction, which led to a decrease in ubiquitination levels of p53, consequently resulting in the increased p53 stabilization. The increase in phosphorylation of p53 at Thr18 presumably contributed to the weakened p53-Mdm2 interaction.
Viral proteins play important roles in resistance to host anti-viral effects, especially its non-structural protein NS1 have played a variety of important functions during the intracellular signaling pathway. In interferon deficient Vero cells, p53 luciferase activities were detected by co-transfection experiments and dual reporter genes system. The results showed that NS1 inhibits the activity of p53 remarkably. However, NS1 does not affect the p53 protein levels and subcellular localization as detected by western-blotting and indirect immunofluorescence assay. NS1 and p53 were co-transfected into H1299 cells, apoptosis were detected by flow cytometry and apoptosis detection kit TUNNEL. The results showed that NS significantly inhibits p53-mediated apoptosis. To construct different deletion mutants of NS1, modified PCR-based site-directed mutagenesis was performed. To screen domain responsible for inhibiting p53 activity, p53 luciferase activity were detected by dual reporter gene systems. The results showed that the 144-188 amino acid of NS1 protein is a key domain responsible for inhibiting p53 activity. The flag-NS1-△144/188 did not inhibit p53 activity. Furthermore, the flag-NS1-△144/188 was unable to inhibit p53-mediated apoptosis. H1299 cells were co-transfected with GFP-p53 and Flag-NS1-wt or flag-NS1-△144/188 respectively. The results showed that NS1 associates with p53, and flag-NS1-△144/188 mutant was also able to bind p53 as detected by Co-IP experiment. So NS1 bound to p53 was one of mechanisms underlying the inhibition of p53 activity, the 144-188 domain of NS1 protein is an inhibitory domain but not a binding domain.
In addition, viral protein NP was found to activate p53 activity, but did not activate p53 mediated apoptosis. It regulated the activity of p53 by competing with the NS1. The domain responsible for activating p53 was located at the C-terminal of NP. The detailed mechanism and the biological significance of activation p53 by NP need uncover in the future.
Finally,this study analysis the mechanism of dynamics of p53 activity in influenza virus infected cells, the virus proteins involved in regulating p53 activity. This may be one of the mechanisms that influenza viruses escaped host innate immune. Those researches provided theoretical basis for study of anti-influenza virus drug develop- ment and model for influenza virus and host-cells interaction researches in the future.
引文
1.萨姆布鲁克J,拉塞尔DW.《分子克隆实验指南(中文版)》(第三版)(上、下册),科学出版社。
2.沈阳.猪流感病毒感染细胞的p53蛋白变化及生物学活性分析[博士学位论文] .北京:中国农业科学院研究生院,2009.
3.殷震和刘景华.动物病毒学.1997, p:704-730.
4. Abida W M, Nikolaev A, Zhao W, Zhang W, Gu W. FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J. Biol. Chem. 2007, 282: 1797-1804.
5. Agustin P, Paul D. The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 2002, 83: 723-734.
6. Allison S J, Jiang M, Milner J. Oncogenic viral protein HPV E7 upregulates the SIRT1 longivity protein in human cervical cancer cells. Aging 2009, 1: 316-327.
7. An W, Kim J, Roeder R G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 2004, 117: 735-748.
8. Appella E, Anderson C W. Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 2001, 268: 2764-2772.
9. Aragon T, de la Luna S, Novoa I, Carrasco L, Ortin J, Nieto A. Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol Cell Biol 2000, 20: 6259-6268.
10. Arzt S, Petit I, Burmeister W P, Ruigrok R W, Baudin F. Structure of a knockout mutant of influenza virus M1 protein that has altered activities in membrane binding, oligomerisation and binding to NEP (NS2). Virus Res 2004, 99: 115-119.
11. Ashcroft M, Kubbutat M H, Vousden K H. Regulation of p53 function and stability by phosphorylation. Mol. Cell. Biol. 1999, 19: 1751-1758.
12. Ayed A, Mulder F A, Yi G S, Lu Y, Kay L E, Arrowsmith C H. Latent and active p53 are identical in conformation. Nat. Struct. Biol. 2001, 8: 756-760.
13. Bancroft C T, Parslow T G. Evidence for segment-nonspecific packaging of the influenza a viru genome. J Virol 2002, 76(14): 7133-7139.
14. Barboza J A, Iwakuma T, Terzian T, El-Naggar A K, Lozano G. Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol. Cancer Res. 2008, 6: 947-954.
15. Benjamin G H, Richard E R, Juan O, David J. The multifunctional NS1 protein of influenza A viruses. J Gen Virol 2008, 89: 2359-2376.
16. Bergamaschi D, Samuels Y, O’Neil N J, Trigiante G, Crook T, Hsieh J K, O’Connor D J, Zhong S, Campargue I, Tomlinson M L, Kuwabara P E, Lu X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 2003, 33: 162-167.
17. Berns K, Hijmans E M, Mullenders J, Brummelkamp T R, Velds A, Heimerikx M, Kerkhoven R M,Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley P S, Beijersbergen R L, Bernards R. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 2004, 428: 431-437.
18. Biswas S K, Nayak D P. Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol 1994, 68:1819-1826.
19. Blattner C, Tobiasch E, Litfen M, Rahmsdorf H J, Herrlich P. DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene 1999, 18: 1723- 1732.
20. Bornholdt Z A, Prasad B V. X-ray structure of influenza virus NS1 effector domain. Nat Struct Mol Biol 2006, 13: 559-560.
21. Bourdon J C, Renzing J, Robertson P L, Fernandes K N, Lane, D P. Scotin. a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J Cell Biol 2002, 158: 235-246,.
22. Brooks C L, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell Biol. 2003, 15: 164-171.
23. Brooks C L, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 2006, 21: 307-315.
24. Brummelkamp T R, Fabius A W, Mullenders J, Madiredjo M, Velds A, Kerkhoven R M, Bernards R, Beijersbergen R L. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nat. Chem. Biol. 2006, 2: 202-206.
25. Budanov A V, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008, 134: 451-460.
26. Bui M, Whittaker G, Helenius A. The effect of M1 protein and low pH on nuclear transport of influenza virus vRNPs. J Virol 1996, 70: 8391-8401.
27. Burgui, I, Aragon T, Ortin J, Nieto A. PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. J Gen Virol 2003, 84: 3263-3274.
28. Bussey K A, Bousse T L, Desmet E A, Kim B, Takimoto T. PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol. 2010,Feb 24.
29. Canman C E, Lim D S, Cimprich K A, Yaya Y, Tamai K, Sakaguchi K, Appella E, Kastan M Siliciano J D. Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53. Science 1998, 281: 1677-1679
30. Cain C, Miller S, Ahn J, Prives C. The N terminus of p53 regulates its dissociation from DNA. J. Biol. Chem. 2000, 275: 39944-39953.
31. Carter S, Bischof O, Dejean A, Vousden K H. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat. Cell Biol. 2007, 9: 428-435.
32. Castiglioni P, Hall D S, Jacovetty E L, Ingulli E, Zanetti M. Protection against influenza A virus by memory CD8 T cells requires reactivation by bone marrow-derived dendritic cells. J Immunol 2008, 180: 4956-4964.
33. Cauthen A N, Swayne D E, Sekellick M J, Marcus P I, Suarez D L. Amelioration of influenza virus pathogenesis in chickens attributed to the enhanced interferon-inducing capacity of a virus with atruncated NS1 gene. J Virol 2007, 81: 1838-1847.
34. Cawley S, Bekiranov S, Ng HH, Kapranov P, Sekinger EA, Kampa D, Piccolboni A, Sementchenko V, Cheng J, Williams AJ, Wheeler R, Wong B, Drenkow J, Yamanaka M, Patel S, Brubaker S, Tammana H, Helt G, Struhl K, Gingeras TR.Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 2004, 116, 499-509.
35. Cecconi F, Alvarez-Bolado G, Meyer B I, Roth K A, Gruss P. Apaf1(CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998, 94: 727-737.
36. Chan W M, Mak M C, Fung T K, Lau A, Siu W Y, Poon R Y. Ubiquitination of p53 at multiple sites in the DNA-binding domain. Mol. Cancer Res. 2006, 4: 15-25.
37. Chao C, Wu Z, Mazur S J, Borges H, Rossi M, Lin T, Wang J Y, Anderson C W, Appella E, Xu Y. Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. Mol. Cell.Biol. 2006, 26: 6859-6869.
38. Chen W, Calvo P A, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med. 2001, 7: 1306-1312.
39. Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005, 121: 1071-1083.
40. Chien C Y, Xu Y, Xiao R, Aramini J M, Sahasrabudhe P V, Krug R M, Montelione G T. Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. Biochemistry 2004, 43: 1950-1962.
41. Chipuk J E, Kuwana T, Bouchier-Hayes L, Droin N M, Newmeyer D D, Schuler M, Green D R. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004, 303: 1010-1014.
42. Cheung C Y, Poon L L, Lau A S, Luk W, Lau Y L, Shortridge K F, Gordon S, Guan Y, Peiris J S. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002, 360: 1831-1837.
43. Cho Y, Gorina S, Jeffrey P D, Pavletich N P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 1994, 265: 346-355.
44. Chuikov S, Kurash J K, Wilson J R, Xiao B, Justin N, Ivanov G S, McKinney K, Tempst P, Prives C, Gamblin S J, Barlev N A, Reinberg D. Regulation of p53 activity through lysine methylation. Nature 2004, 432: 353-360.
45. Coleman J Robert. The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages. Virology J 2007, 4: 9.
46. Colman P M, Varghese J N, Laver W G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983, 303(5912): 41-44.
47. Conenello G M, Zamarin D, Perrone L A, Tempey T, Palese P. A single mutation in the PB1-F2 of
H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PloS Pathog 2007, 3: 1414-1421.
48. Craig A L, Vojtesek B, Mikutowska J, Thompson A, Hupp T R, Burch L.Novel phosphorylation sites of human tumour suppressor protein p53 at Ser20 and Thr18 that disrupt the binding of mdm2 (mouse double minute 2) protein are modified in human cancers. Biochem. J 1999, 342: 133-141
49. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison P R, Gasco M, Garrone O, Crook T, Ryan K M. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006, 126: 121–134.
50. Cummins J M, Rago C, Kohli M, Kinzler K W, Lengauer C, Vogelstein B. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 2004, 428: 1 p following 486.
51. Dai M S, Zeng S X, Jin Y, Sun X X, David L, Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol. Cell. Biol. 2004, 24: 7654-7668.
52. Das S, Raj L, Zhao B, Bernstein A, Aaronson S A, Lee S W. Hzf, a key modulator of p53 mediated transcription, functions as a critical determinant of cell survival and death upon genotoxic stress. Cell 2007130, 624-637.
53. de la Luna S, Fortes P, Beloso A, Ortin J. Influenza virus NS1 protein enhances the rate of translation initiation of viral mRNAs. J Virol 1995, 69: 2427-2433.
54. de Jong M D, Simmons C P, Thanh T T, Hien V M, Smith G J D, Chau T N B, Hoang D M, Chau N V V, Khanh T H, Dong V C, Qui Ph T, Cam B V, HaD Q, Guan Y, Peiris J S M, Chinh N T, Hien T T, Farrar J. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Medicine 2006, 12: 1203-1207.
55. Digard P, Elton D, Bishop K, Medcalf E, Weeds, A, Pope B. Modulation of nuclear localization of the infuenza virus nucleoprotein through interaction with actin filaments. J Virol 1999, 73: 2222- 2231.
56. Donelan N R, Basler C F, Garcia-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol 2003, 77: 13257-13266.
57. Dornan D, Wertz I, Shimizu H, Arnott D, Frantz G D, Dowd P, O’Rourke K, Koeppen H, Dixit V M. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004, 429: 86-92.
58. Eckardt-Michel J, Lorek M, Baxmann D. The fusion protein of respiratory syncytial virus triggers p53-dependent apoptosis. J virol 2008, 82(7): 3236-3249.
59. Ehrhardt C, Wolff T, Pleschka S, Planz O, Beermann W, Bode J G, Schmolke M, Ludwig S. Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses. J Virol 2007, 4: 3058-3067
60. Ekiert D C, Bhabha G, Elsliger M A, Friesen R H, Jongeneelen M, Throsby M, Goudsmit J, Wilson I A. Antibody recognition of a highly conserved influenza virus epitope. Science 2009, 324(5924): 246-51.
61. Elmore L W, Chang S F, Wang X W, Chang S,Callahan C P, Geller D A, Will H, Harris C C, Hancock A R. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl. Acad. Sci. U S A.1997, 94: 14707-14712.
62. Enami K, Sato T A, Nakada S, Enami M. Influenza virus NS1 protein stimulates translation of the M1 protein. J Virol 1994, 68: 1432-1437.
63. Enami M, Enami K. Characterization of influenza virus NS1 protein by using a novel helper-virus-free reverse genetic system. J Virol 2000, 74: 5556-5561.
64. Falcon A M, Fortes P, Marion R M, Beloso A, Ortin J. Interaction of influenza virus NS1 protein and the human homologue of Staufen in vivo and in vitro. Nucleic Acids Res 1999, 27: 2241–2247.
65. Fang S, Jensen J P, Ludwig R L, Vousden K H, Weissman A M. Mdm2 is a RING finger- dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 2000, 275: 8945-8951.
66. Feng L, Lin T, Uranishi H, Gu W, Xu Y. Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol. Cell. Biol. 2005, 25: 5389-5395.
67. Fernandez-Sesma A, Marukian S, Ebersole B J, Kaminski D, Park M S, Yuen T, Sealfon S C, Garcia-Sastre A, Moran T M. Influenza virus evades innate and adaptive immunity via the NS1 protein. J Virol 2006, 80: 6295-6304.
68. Flatt P M, Polyak K, Tang L J, Scatena C D, Westfall MD, Rubinstein LA, Yu J, Kinzler KW, Vogelstein B, Hill DE, Pietenpol JA. p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest. Cancer Lett 2000, 156: 63-72.
69. Fortes P, Beloso A, Ortin J. Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport. EMBO J 1994, 13, 704-712.
70. Gabriel G, Herwig A, Klenk H D. Interaction of polymerase subunit PB2 and NP with importin a1 is a determinant of host range of influenza A virus. PLoS Pathog 2008, 4, e11.
71. Gabriele N, Takeshi N., Yoshihiro K. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 2009, 459: 931-939.
72. Gack M U, Albrecht R A, Urano T, Inn K S, Huang I C, Carnero E, Farzan M, Inoue S, Jung J U, García-Sastre A. Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I. Cell Host Microbe 2009, 5(5): 439-49.
73. Gambotto A, Barratt-Boyes S M, de Jong M D, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet 2008, 371(9622):1464-75.
74. Garaigorta U, Ortin J. Mutation analysis of a recombinant NS replicon shows that influenza virus NS1 protein blocks the splicing and nucleo-cytoplasmic transport of its own viral mRNA. Nucleic Acids Res 2007, 35: 4573-4582.
75. Garcia-Cao I, Garcia-Cao M, Martin-Caballero M, Criado L M, Klatt P, Flores J M, Weill J, Blasco M A, Serrano M. "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 2002, 21: 6225-6235.
76. Garcia M A, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M. Impact of protein kinasePKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 2006, 70: 1032-1060.
77. Geiss G K, Salvatore M, Tumpey T M, Carter V S, Wang X, Basler C F Taubenberger J K. Bumgarner R E, Palese P, Katze M G, García-Sastre A. Cellular transcriptional profiling in influenza A virus infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A. 2002, 99: 1073641.
78. Gharbi S I, Zvelebil M J, Shuttleworth S J, Hancox T, Saghir N, Timms J F, Waterfield M D. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007, 404: 15-21.
79. Gibbs J S, Malide D, Hornung F, Bennink J R, Yewdell J W. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol 2003, 77, 7214-7224.
80. Goodman R H, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000, 14: 1553-1577.
81. Green D R, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009, 458(7242):1127-30.
82. Grossman S R, Deato M E, Brignone C, Chan H M, Kung A L, Tagami H, Nakatani Y, Livingston D M. Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300. Science 2003, 300: 342-344.
83. Groskreutz D J, Monick M M, Yarovinsky T O, Powers L S, Quelle D E, Varga S M, Look D C, Hunninghake G W. Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells. J Immunol 2007, 179: 2741-2747.
84. Gu W, Roeder R G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997, 90: 595-606.
85. Guo Z, Chen L M, Zeng H, Gomez J A, Plowden J, Fujita T, Katz J M, Donis R O, Sambhara S. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am J Respir Cell Mol Biol 2007, 36: 263-269.
86. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv. Cancer Res. 2000, 77: 81-137.
87. Hale B G, Jackson D, Chen Y H, Lamb R A, Randall R E. Influenza A virus NS1 protein binds p85b and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad Sci U S A 2006, 103: 14194 -14199.
88. Hale B G, Barclay W S, Randall R E, Russell R J.Structure of an avian influenza A virus NS1 protein effector domain. Virology 2008a, 378: 1-5.
89. Hale B G, Batty I H, Downes C P, Randall R E.Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation. J. Biol. Chem. 2008b, 283:1372-1380.
90. Hale B G, Randall R E, Ort?′n J, Jackson D. The multifunctional NS1 protein of influenza viruses. Journal of General Virology 2008c, 89: 2359-2376
91. Harris C C. p53 Tumor suppressor gene: from the basic research laboratory to the clinic– an abridged historical perspective. Carcinogenesis 1996, 17: 1187-1198.
92. Hatada E, Hasegawa M, Shimizu K, Hatanaka M, Fukuda R. Analysis of influenza A virus temperature-sensitive mutants with mutations in RNA segment 8. J Gen Virol 1990, 71: 1283-1292.
93. Hatada E, Saito S, Fukuda R. Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells. J Virol 1999, 73: 2425-2433.
94. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997, 387: 296-299.
95. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci 2003, 116: 4077-4085.
96. Hayman A, Comely S, Lackenby A, Murphy S, McCauley J, Goodbourn S, Barclay W. Variation in the ability of human influenza A viruses to induce and inhibit the IFN-βpathway. Virology 2006, 347: 52-64.
97. Hayman A, Comely S, Lackenby A, Hartgroves L C, Goodbourn S, McCauley J W, Barclay W S. NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response. J Virol 2007, 81: 2318-2327.
98. Heikkinen L S, Kazlauskas A, Melen K, Wagner R, Ziegler T, Julkunen I, Saksela K. Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. J. Biol. Chem. 2008, 283: 5719-5727.
99. Hermeking H, Lengauer C, Polyak K, He T C, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B.
14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997, 1: 3-11.
100. Hoffmann E, Stech J, Guan Y, Webster R G, Perez D R. Universal primer set for the full-length amplification of all influenza viruses. Arch. Virol. 2001, 146: 2275-2289.
101. Holowaty M N, Frappier L. HAUSP/USP7 as an Epstein–Barr virus target. Biochemical Society Transactions 2004, 32(5): 731-734.
102. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997, 420: 25-27.
103. Honda R, Yasuda H. Association of p19 (ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999, 18: 22-27.
104. Huang J, Perez-Burgos L, Placek B J, Sengupta R, Richter M, Dorsey J A, Kubicek S, Opravil S, Jenuwein T, Berger S L. Repression of p53 activity by Smyd2-mediated methylation. Nature 2006, 444: 629-632.
105. Huang J, Sengupta R, Espejo A B, Lee M G, Dorsey J A, Richter M, Opravil S, Shiekhattar R, Bedford M T, Jenuwein T, Berger S L. p53 is regulated by the lysine demethylase LSD1. Nature 2007, 449: 105-108.
106. Hyland L, Webby R, Sandbulte M R, Clarke B, Hou S. Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model. Virology 2006, 349: 156-163.
107. Itahana K, Mao H, Jin A, Itahana Y, Clegg H V, Lindstrom M S, Bhat K P, Godfrey V L, Evan G I,Zhang Y. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 2007, 12: 355-366.
108. Itoh M, Hotta H. Structure, function and regulation of expression of influenza virus matrix M1 protein. Nippon. Rinsho 1997, 55(10): 2581-2586.
109. Ito A, Lai C H, Zhao X, Saito S, Hamilton M H, Appella E, and Yao T P. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 2001, 20: 1331-1340.
110. Iwakuma T, Lozano G. Crippling p53 activities via knock-in mutations in mouse models. Oncogene 2007, 26: 2177-2184.
111. Iyer N G, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene 2004, 23: 4225-4231.
112. Jackson D, Hossain M J, Hickman D, Perez D R, Lamb R A. A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc Natl Acad Sci U S A 2008, 105: 4381-4386.
113. Jansson M, Durant S T, Cho E C, Sheahan S, Edelmann M, Kessler B, La Thangue N B. Arginine methylation regulates the p53 response. Nat. Cell Biol. 2008, 10: 1431-1439.
114. Jenuwein T, Allis C D. Translating the histone code. Science. 2001, 293: 1074-1080.
115. Jiao P, Tian G, Li Y, Deng G, Jiang Y, Liu C, Liu W, Bu Z, Kawaoka Y, Chen H. A single-amino- acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 2008, 82: 1146-1154.
116. Johnson T M, Hammond E M, Giaccia A, Attardi L D. The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality. Nat. Genet. 2005, 37: 145-152.
117. Jones S N, Roe A E, Donehower L A, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 1995, 378: 206-208.
118. Kaeser M D, Iggo R D. Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl. Acad. Sci. U S A 2002, 99: 95-100.
119. Kemler I, Whittaker G, Helenius A. Nuclear import of microinjected influenza virus ribonucleoproteins. Virology 1994, 202: 1028-1033,
120. Kern S E, Kinzler K W, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequence-specific DNA binding protein. Science 1991, 252: 1708-1711.
121. Kim E, Rohaly G, Heinrichs S, Gimnopoulos D, Meissner H, Deppert W. Influence of promoter DNA topology on sequence-specific DNA binding and transactivation by tumor suppressor p53. Oncogene 1999, 18: 7310-7318.
122. Kim J E, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008, 451: 583-586.
123. Knights C D, Catania J, Di Giovanni S, Muratoglu S, Perez R, Swartzbeck A, Quong A A, Zhang X, Beerman T, Pestell R G, Avantaggiati M L. Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. J. Cell Biol. 2006, 173: 533-544.
124. Kochs G, Garcia-Sastre A, Martinez-Sobrido L. Multiple anti-interferon actions of the influenza Avirus NS1 protein. J Virol 2007a, 81: 7011-7021.
125. Kochs G, Koerner I, Thiel L, Kothlow S, Kaspers B, Ruggli N, Summerfield A, Pavlovic J, Stech J, Staeheli P. Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J Gen Virol 2007b, 88: 1403-1409.
126. Kok K H, Jin D Y. Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells. J Gen Virol 2006, 87: 2639-2644.
127. Krug R M, Yuan W, Noah D L, Latham A G. Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein. Virology 2003, 309:181-189.
128. Krummel K A, Lee C J, Toledo F, Wahl G M. The C-terminal lysines fine-tune P53 stress responses in a mouse model but are not required for stability control or transactivation. Proc. Natl. Acad. Sci. U S A 2005, 102: 10188-10193.
129. Kruse J P, Gu W. MSL2 promotes MDM2 independent cytoplasmic localization of p53. J. Biol. Chem. 2008a 284, 3250-3263.
130. Kruse J P, Gu W. SnapShot: p53 posttranslational modifications. Cell 2008b, 133: 930.
131. Kruse J P, Gu W. Modes in p53 regulation. Cell 2009, 137: 609-622.
132. Kubbutat M H, Jones S N, Vousden K H. Regulation of p53 stability by Mdm2. Nature 1997, 387: 299-303.
133. Kurokawa M, Koyama A H, Yasuoka, S, Adachi AInfluenza virus overcomes apoptosis by rapid multiplication. Int J Mol Med 1999, 3: 527-530.
134. Lain S, Hollick J J, Campbell J, Staples O D, Higgins M, Aoubala M, McCarthy A, Appleyard V, Murray KE, Baker L, Thompson A, Mathers J, Holland S J, Stark M J, Pass G, Woods J, Lane D P, Westwood N J. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008, 13: 454-463.
135. Lamb R A, Takeda M. Death by influenza virus protein. Nat Med. 2001, 7(12):1306-12.
136. Laptenko O, Prives C. Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ. 2006, 13: 951-961.
137. Leng R P, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant J M, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003, 112: 779-791.
138. Leu J I, Dumont P, Hafey M, Murphy M E, George D L. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol. 2004, 6: 443-450.
139. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008, 132: 27-42.
140. Licheng S, Summers D F, Peng Q, Galarza J M. Influenza A virus polymerase subunit PB2 is the endonuclease which cleaves host cell mRNA and functions only as the trimeric enzyme. Virology 1995, 208: 38-47.
141. Li L, Guo L, Tao Y, , Zhou S, Wang Z, Luo W, Hu D, Li Z, Xiao L, Tang M, Yi W, Tsao S W, Cao Y. Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases. Cancer Letters 2007, 255 (2): 219-231.
142. Li M, Chen D, Shiloh A, Luo J, Nikolaev A Y, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002a, 416: 648-653.
143. Li M, Luo J, Brooks C L, Gu W. Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem. 2002b, 277: 50607-50611.
144. Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol. Cell 2004, 13: 879-886.
145. Li S, Min J Y, Krug R M, Sen G C. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 2006, 349: 13-21
146. Li X, Qiu Y, Shen Y, Ding C, Liu P, Zhou J, Ma Z. Splicing together different regions of a gene by modified polymerase chain reaction-based site-directed mutagenesis. Anal Biochem. 2008, 373(2):398-400.
147. Li Y, Anderson D H, Liu Q, Zhou Y. Mechanism of influenza A virus NS1 protein interaction with the p85β, but not the p85α, subunit of PI3K and up-regulation of PI3K activity. J. Biol. Chem. 2008, 283: 23397-23409.
148. Li Z, Jiang Y, Jiao P, Wang A, Zhao F, Tian G, Wang X, Yu K, Bu Z, Chen H. The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J Virol 2006, 80: 11115-11123.
149. Linares L K, Hengstermann A, Ciechanover A, Muller S, Scheffner M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl. Acad. Sci. U S A 2003, 100: 12009-12014.
150. Ling Bai, Wei-Guo Zhu. p53: Structure, Function and Therapeutic Applications. Journal of Cancer Molecules 2006, 2(4): 141-153,
151. Lipatov A S, Andreansky S, Webby R J, Hulse D J, Rehg J E, Krauss S, Perez D R, Doherty P C, Webster R G, Sangster M Y. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol 2005, 86: 1121- 1130.
152. Liu X, Yue P, Khuri F R, Sun S Y. p53 upregulates death receptor 4 expression through an intronic p53 binding site. Cancer Res 2004, 64: 5078-5083.
153. Liu L, Scolnick D M, Trievel R C, Zhang H B, Marmorstein R, Halazonetis T D, Berger S L. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol. Cell. Biol. 1999, 19: 1202-1209.
154. Liu Y, Lagowski J P, Vanderbeek G E, Kulesz-Martin M F. Facilitated search for specific genomic targets by p53 C-terminal basic DNA binding domain. Cancer Biol. Ther. 2004, 3: 1102-1108.
155. Llanos S, Clark P A, Rowe J, Peters G. Stabilization of p53 by p14 (ARF) without relocation of MDM2 to the nucleolus. Nat. Cell Biol. 2001, 3: 445-452.
156. Lohrum M A, Woods D B, Ludwig R L, Balint E, Vousden K H. C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell. Biol. 2001, 21: 8521-8532.
157. Lohrum M A, Ludwig R L, Kubbutat M H, Hanlon M, Vousden K H. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 2003, 3: 577-587.
158. Long J X, Peng D X, Liu Y L, Wu Y T, Liu X F. Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. Virus Genes 2008, 36: 471-478.
159. Lowe S W, Sherr C J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr. Opin. Genet. Dev. 2003, 13: 77-83.
160. Lu X, Ma O, Nguyen T A, Jones S N, Oren M, Donehower L A. The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 2007, 12: 342-354.
161. Ludwig S, Wang W, Ehrhardt C, Zheng H, Donelan N, Planz O, Pleschka S, García-Sastre A, Heins G, Wolff T. The influenza A virus NS1 protein inhibits activation of the jun N-terminal kinase and AP-1 transcription factors. J Virol 2002, 76: 11166-11171.
162. Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000, 408: 377-381.
163. Luo J, Nikolaev A Y, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001, 107: 137-148.
164. Marchenko N D, Moll U M. The role of ubiquitination in the direct mitochondrial death program of p53. Cell Cycle 2007a, 6: 1718-1723.
165. Marchenko N D, Wolff S, Erster S, Becker K, Moll U M. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 2007b, 26: 923-934.
166. Marion R M, Aragon T, Beloso A, Nieto A, Ortin J. The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res 1997a, 25: 4271-4277.
167. Marion R M, Zurcher T, de la Luna S, Ortin J. Influenza virus NS1 protein interacts with viral transcription-replication complexes in vivo. J Gen Virol 1997b, 78: 2447-2451.
168. Marine J C, Jochemsen A G. Mdmx as an essential regulator of p53 activity. Biochem. Biophys. Res. Commun. 2005, 331: 750-760.
169. Marine J C, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006, 13: 927-934.
170. Martin K, Helenius A. Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell 1991, 67: 117-130.
171. Massin P, van der Werf S, Naffakh N. Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol 2001, 75(11):5398-404.
172. Matrosovich M N, Matrosovich T Y, Gray T, Roberts N A, Klenk H D.Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 2004, 78 (22): 12665-7.
173. Matskevich A A, Moelling K. Dicer is involved in protection against influenza A virus infection. J Gen Virol 2007, 88: 2627-2635.
174. Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H. p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 2002, 62: 2883-2889.
175. Mayo L D, Donner D B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. TrendsBiochem. Sci. 2002, 27: 462-467.
176. McAuley J L, Hornung F, Boyd K L, Smith A M, McKeon R, Bennink J, Yewdell J W,McCullers J A. Expression of the 1918 Influenza A Virus PB1-F2 Enhances the Pathogenesis of Viral and Secondary Bacterial Pneumonia. Cell Host Microbe 2007, 2:240-249.
177. Meek D W. The p53 response to DNA damage. DNA Repair (Amst.) 2004, 3: 1049-1056.
178. Melchior F, Hengst L. SUMO-1 and p53. Cell Cycle 2002, 1: 245-249.
179. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen A G. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 2005, 4: 1166-1170.
180. Melen K, Kinnunen L, Fagerlund R, Ikonen N, Twu K Y, Krug R M, Julkunen I. Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes. J Virol 2007, 81: 5995-6006.
181. Mibayashi M, Martinez-Sobrido L, Loo Y M, Cardenas W B, Gale M Jr, Garcia-Sastre A. Inhibition of retinoic acidinducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 2007, 81: 514-524.
182. Michael D, Oren M. The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol. 2003, 13: 49-58.
183. Migliorini D, Denchi E L, Danovi D, Jochemsen A, Capillo, M, Gobbi A, Helin K, Pelicci P G, Marine J C. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol. Cell. Biol. 2002, 22: 5527-5538.
184. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll U M. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 2003, 11: 577-590.
185. Min J Y, Krug R M. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2’-5’oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A, 2006, 103: 7100-7105.
186. Min J Y, Li S, Sen, G C, Krug R M. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 2007, 363, 236-243.
187. Minsky N, Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol. Cell 2004, 16: 631-639.
188. Montes de Oca Luna R., Wagner D S, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 1995, 378: 203-206.
189. Morris S J, Price G E, Barnett J M, Hiscox S A, Smith H, Sweet C. Role of neuraminidase in influenza virus-induced apoptosis. J Gen. Virol. 1999, 80: 137-146.
190. Munoz-Fontela C, Garcia MA, Garcia-Cao I, Collado M, Arroyo J, Esteban M, Serrano M, Rivas C. Resistance to viral infection of super p53 mice. Oncogene 2005, 24: 3059-3062.
191. Nakano K, Vousden K H. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001, 7: 683-694.
192. Narayanan K, Chen C J, Maeda J, Makino S. Nucleocapsid-independent specific viral RNApackaging via viral envelope protein and viral RNA signal. J Virol 2003, 77(5): 2922-7.
193. Neumann G, Brownlee G G, Fodor E, Kawaoka Y. Orthomyxovirus replication, transcription, and polyadenylation. Curr Top Microbiol Immunol. 2004, 283: 121-43.
194. Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 2009, 459: 931-939.
195. Nicole C R, Matt S, Frank T V, Ervin F. NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol 2009, 90: 1398-1407.
196. Noah D L, Twu K Y, Krug R M. Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 39 end processing of cellular pre-mRNAS. Virology 2003, 307: 386-395.
197. Obenauer J C, Denson J, Mehta P K, Su X, Mukatira S, Finkelstein D B, Xu X, Wang J, Ma J, Fan Y, Rakestraw Y M, Webster R G, Hoffmann E, Krauss S, Zheng J, Zhang Z, Naeve C W. Large- scale sequence analysis of avian influenza isolates. Science 2006, 311: 1576-1580.
198. O'Connor L, Harris A W, Strasser A. CD95 (Fas/APO-1) and p53 signal apoptosis independently in diverse cell types. Cancer Res 2000, 60: 1217-1220.
199. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000, 288: 1053-1058.
200. Ohkubo S, Tanaka T, Taya Y, Kitazato K, Prives C. Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription. J. Biol. Chem. 2006, 281: 16943–16950.
201. Oleg P Z, Hans-Dieter K. Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis 2007, 12: 1419-1432.
202. O’Neill R E, Jaskunas R, Blobel G, Palese P, Moroianu J. Nuclear import of infuenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. J. Biol. Chem. 1995, 270: 22701-22704.
203. O’Neill R E, Talon J, Palese P. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 1998, 17: 288-296.
204. Opitz B, Rejaibi A, Dauber B, Eckhard J, Vinzing M, Schmeck B, Hippenstiel S, Suttorp N, Wolff T. IFN-βinduction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 2007, 9: 930-938.
205. Oren M, Rotter, V. Introduction: p53–the first twenty years. Cell. Mol. Life Sci. 1999, 55: 9-11.
206. Oren M. Decision making by p53: life, death and cancer. Cell Death Differ 2003, 10: 431-442.
207. Palese P, Shaw M L. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams &Wilkins; 2007.
208. Parant J, Chavez-Reyes A, Little N A, Yan W, Reinke V, Jochemsen A G, Lozano G. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat. Genet. 2001, 29: 92-95.
209. Park Y W, Katze M G. Translational control by influenza virus. Identification of cis-actingsequences and trans-acting factors which may regulate selective viral mRNA translation. J. Biol. Chem. 1995, 270: 28433-28439.
210. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi P P, Pelicci P G. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000, 406, 207-210.
211. Pichlmair A, Schulz O, Tan C P, Naslund T I, Liljestrom P, Weber F, Reis e Sousa C. RIG-I- mediated antiviral responses to single-stranded RNA bearing 59-phosphates. Science 2006, 314: 997-1001.
212. Portela A and Digard P. The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 2002, 83: 723-734.
213. Poyurovsky M V, Priest C, Kentsis A, Borden K L, Pan Z Q, Pavletich N, Prives C. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 2007, 26: 90-101.
214. Qiu Y, Krug R M. The influenza virus NS1 protein is a poly(A)-binding protein that inhibits nuclear export of mRNAs containing poly(A). J Virol 1994, 68: 2425-2432.
215. Quinlivan M, Zamarin D, Garcia-Sastre A, Cullinane A, Chambers T, Palese P. Attenuation of equine influenza viruses through truncations of the NS1 protein. J Virol 2005, 79: 8431-8439.
216. Randall R E, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008, 89: 1-47.
217. Ringshausen I, O’Shea C C, Finch A J, Swigart L B, Evan G I. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006, 10: 501-514.
218. Rivas C, Aaronson S A, Munoz-Fontela C. Dual role of p53 in innate antiviral immunity. Viruses 2010, 2: 298-313.
219. Roth J, Dobbelstein M, Freedman D A, Shenk T, Levine A J. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 1998, 17: 554-564.
220. Sakaguchi K, Herrera J E, Saito S, Miki T, Bustin M, Vassilev A, Anderson C W, and Appella E. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 1998, 12: 2831-2841.
221. Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson C W, Appella E. Damage-mediated phosphorylation of human p53threonine 18 through a cascade mediated by a casein 1-like kinase effect on Mdm2 binding. J. Biol. Chem. 2000, 275: 9278-9283.
222. Salomon R, Franks J, Govorkova EA, Ilyushina N A., Yen H L, Hulse-Post D J, Humberd J, Trichet M, Rehg J E., Webby R J., Webster R G, Hoffmann E. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 2006, 203: 689-697.
223. Salvatore, M., Basler, C. F., Parisien, J. P., Horvath, C. M., Bourmakina, S., Zheng, H., Muster, T., Palese, P. & Garcia-Sastre, A. Effects of influenza A virus NS1 protein on protein expression: theNS1 protein enhances translation and is not required for shutoff of host protein synthesis. J Virol 2002, 76: 1206-1212.
224. Samuels-Lev Y, O’Connor D J, Bergamaschi D, Trigiante G, Hsieh J K, Zhong S, Campargue I, Naumovski L, Crook T, and Lu X. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 2001, 8: 781-794.
225. Sanz-Ezquerro J J, Zurcher T, de la Luna S, Ortin J, and Nieto A. The amino-terminal one-third of the influenza virus PA protein is responsible or the induction of proteolysis. J Virol 1996, 70: 1905 -1911.
226. Sarah L N, Elizabeth M, Dawn F, Anne E M, Debra E Paul D. Identification of the domains of the influenza A virus M1 matrix protein required for NP binding, oligomerization and incorporation into virions. J Gen Virol 2007, 88: 2280-2290.
227. Satterly N, Tsai P L, van Deursen J, Nussenzveig D R, Wang Y, Faria P A, Levay A, Levy D E, Fontoura B M. Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc Natl Acad Sci U S A 2007, 104: 1853-1858.
228. Scheffner M, Huibregtse J M, Vierstra R D, Howley P M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993, 75, 495-505.
229. Schon O, Friedler A, Bycroft M, Freund S M, Fersht, A R. Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 2002, 323(3): 491-501.
230. Shangary S, Qin D, McEachern D, Liu M, Miller R S, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah R B, Pienta K J, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl. Acad. Sci. U S A 2008, 105: 3933-3938.
231. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol. 2009, 49: 223-241.
232. Shapira S D, Gat-Viks I, Shum B O, Dricot A, de Grace M M, Wu L, Gupta P B, Hao T, Silver S J, Root D E, Hill D E, Regev A, Hacohen N. A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection. Cell 2009, 139(7):1255-67.
233. Shen Y, Wang X, Guo L, Qiu Y, Li X, Yu H, Xiang H, Tong G, Ma Z. Influenza A virus induces p53 accumulation in a biphasic pattern. Biochem Biophys Res Commun. 2009, 382(2): 331-335.
234. Sherr C J. Divorcing ARF and p53: an unsettled case. Nat. Rev. Cancer 2006, 6: 663-673.
235. Shi X, Kachirskaia I, Yamaguchi H, West L E, Wen H, Wang E W, Dutta S, Appella E, Gozani O. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 2007, 27: 636-646.
236. Shieh S Y, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1997, 91: 325-334.
237. Shieh S Y, Ahn J, Tamai K, Taya Y, Prives C. The human homologs of checkpoint kinases Chk1and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 2000, 14: 289-300.
238. Shin Y K, Liu Q, Tikoo S K, Babiuk L A , Zhou Y. Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 2007a, 88: 13-18.
239. Shin Y K, Li Y, Liu Q, Anderson D H, Babiuk L A, Zhou Y. SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signalling pathway activation. J Virol 2007b, 81: 12730-12739.
240. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006, 440(7083): 435-436.
241. Sieczkarski S B, Whittaker G R. Viral entry. Curr Top Microbiol Immunol. 2005, 285:1–23.
242. Silverman R H. Viral encounters with 2’,5’-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 2007, 81: 12720-12729.
243. Solorzano A, Webby R J, Lager K M, Janke B H, Garcia-Sastre A, Richt J A. Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs. J Virol 2005, 79: 7535-7543.
244. Song M S, Song S J, Kim S Y, Oh H J, Lim D S. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J 2008, 27: 1863-1874.
245. Stegmann T. Membrane fusion mechanisms: the influenza hemagglutinin paradigm and its implications for intracellular fusion. Traffic 2000, 1(8): 598-604。
246. Stevens J, Corper A L, Basler C F, Taubenberger J K, Palese P, Wilson I A. Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus. Science 2004, 33:1866-1870.
247. Stommel J M, Wahl G M. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J 2004, 23: 1547-1556.
248. Sui G, Affar El B, Shi Y, Brignone C, Wall N R, Yin P, Donohoe M, Luke M P, Calvo D, Grossman S R. Yin Yang 1 is a negative regulator of p53. Cell 2004, 117: 859-872.
249. Susana G, Thomas Z, Juan O. Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: a model for the viral RNA polymerase structure. Nucleic Acids Research 1996, 24(22): 4456-4463.
250. Sykes S M, Mellert H S, Holbert M A, Li K, Marmorstein R, Lane W S, McMahon S B. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 2006, 24: 841-851.
251. Szak, S.T., Mays, D., and Pietenpol, J.A. Kinetics of p53 binding to promoter sites in vivo. Mol. Cell. Biol. 2001, 21: 3375-3386.
252. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, Shibue T, Honda K, Taniguchi T. Integration of interferon-α/βsignaling to p53 responses in tumoursuppression and antiviral defence. Nature 2003, 424: 516-523.
253. Takimoto R, El-Deiry W S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNAbinding site. Oncogene 2000, 19: 1735-1743.
254. Talon J, Horvath C M, Polley R, Basler C F, Muster T, Palese P, Garcia-Sastre A. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 2000a, 74: 7989-7996.
255. Wang X, Li M, Zheng H, Muster T, Palese P, Beg A A, Garcia-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kB and induction of alpha/beta interferon. J Virol 2000, 74: 11566-11573.
256. Tanaka T, Ohkubo S, Tatsuno I, Prives C. hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. Cell 2007, 130: 638-650.
257. Tang J, Qu L K, Zhang J, Wang W, Michaelson J S, Degenhardt Y Y, El-Deiry W S, Yang X. Critical role for Daxx in regulating Mdm2. Nat. Cell Biol. 2006a, 8: 855-862.
258. Tang Y, Luo J, Zhang W, and Gu W. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 2006b, 24: 827-839.
259. Tang, Y., Zhao, W., Chen, Y., Zhao, Y., and Gu, W. Acetylation is indispensable for p53 activation. Cell 2008, 133: 612-626.
260. Tarendeau F, Crepin T, Guilligay D, Ruigrok W H, Cusack S, Hart D J. Host determinant residue lysine 627 lies on the surface of a discrete, folded domain of influenza virus polymerase PB2 subunit. PLoS Pathog. 2008, 4, e1000136.
261. Tasdemir E, Maiuri MC , Galluzzi L, Vitale I , Djavaheri-Mergny M, D'Amelio M, Criollo A , Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio J M, Carnuccio R, Moll U M, Madeo F, Paterlini-Brechot P , Rizzuto R, Szabadkai G, Pierron R, Blomgren K , Tavernarakis N, Codogno P , Cecconi F, Kroemer G. Regulation of autophagy by cytoplasmic p53. Nature Cell Biol. 2008, 10: 676-687.
262. Teufel D P, Bycroft M, Fersht A R. Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2. Oncogene 2009, 28(20): 2112-2118.
263. Thornborrow E C, Patel S, Mastropietro A E, Schwartzfarb E M, Manfredi J J. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 2002, 21: 990-999.
264. Tian C, Xing G, Xie P, Lu K, Nie J, Wang J, Li L, Gao M, Zhang L, He F. KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nat. Cell Biol. 2009, 11: 580-591.
265. Timofeeva T A, Klenk H D, Zhirnov O P. Identification of the protease-binding domain in the N-terminal region of influenza virus A matrix protein M1. Mol. Biol. 2001, 35: 411-416.
266. Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C, Pan H, Kessler H, Pancoska P, Moll UM. WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J. Biol. Chem. 2006, 281: 8600-8606.
267. Trigiante G, and Lu X. ASPP [corrected] and cancer. Nat. Rev. Cancer 2006, 6: 217–226.
268. Tumpey T M, Garc?′a-Sastre A, TaubenbergerJ K, Palese P, Swayne D E, Basler C F. Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. U S A 2004, 101: 3166-3171
269. Tumpey T M, Basler C F, Aguilar P V, Zeng H, Solórzano A, Swayne D E, Cox N J, Katz J M, Taubenberger J K, Palese P, García-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005, 310:77-80.
270. Turpin E, Luke K, Jones J, Tumpey T, Konan K, Schultz-Cherry S. Influenza virus infection increases p53 activity: role of p53 in cell death and viral replication. J Virol 2005, 7: 8802-8811.
271. Twu K Y, Noah D L, Rao P, Kuo R L, Krug R M. The CPSF30 binding site on the NS1A protein of influenza A virus s a potential antiviral target. J Virol 2006, 80: 3957-3965.
272. Twu K Y, Kuo R L, Marklund J, Krug R M. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol 2007, 81: 8112-8121.
273. Uldrijan S, Pannekoek W J, Vousden K H. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J 2007, 26: 102-112.
274. Van Hoeven N, Pappas C, Belsera J A., Maines T R., Zeng H, García-Sastre A, Sasisekharan R, Katz J M, Tumpey T M. Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proc. Natl Acad. Sci. U S A 2009, 106:3366-3371.
275. van Riel D, Munster V J, de Wit E, Rimmelzwaan G F, Fouchier R A, Osterhaus A D, Kuiken T. H5N1 virus attachment to lower respiratory tract. Science 2006, 312: 399
276. Vassilev L T, Vu B T, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303: 844-848.
277. Vaziri H, Dessain S K, Ng Eaton E, Imai S I, Frye R A, Pandita T K, Guarente L, Weinberg R A. hSIR2(SIRT1) functions as an NADdependent p53 deacetylase. Cell 2001, 107:149-159.
278. Vogelstein B, Lane D, Levine A J. Surfing the p53 network. Nature 2000,408: 307-310.
279. Wahl G M. Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo. Cell Death Differ. 2006, 13: 973-983.
280. Wang TT, Palese P. Unraveling the mystery of swine influenza virus. Cell, 2009, 137: 983-985.
281. Wang X, Basler C F, Williams B R., Silverman R H, Palese P, Garcia-Sastre A. Functional replacement of the carboxyterminal two-thirds of the influenza A virus NS1 protein with short heterologous dimerization domains. J Virol 2002, 76:12951-12962.
282. Wang X, Taplick J, Geva N, Oren M. Inhibition of p53 degradation by Mdm2 acetylation. FEBS Lett. 2004, 56: 195-201.
283. Watanabe T, Watanabe S, Shinya K, Kim J H, Hatta M, Kawaoka Y. Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. Proc Natl Acad Sci U S A. 2009, 106(2):588-92.
284. Weber J D, Taylor L J, Roussel M F, Sherr C J, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 andactivates p53. Nat. Cell Biol. 1999, 1: 20-26.
285. Whittaker G R. Intracellular trafficking of influenza virus: clinical implications for molecular medicine. Expert Rev Mol Med. 2001, 1: 1-13.
286. Wilson I A, Skehel J J, Wiley D C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3? resolution. Nature 1981, 289(5796):366-373.
287. Wise H M, Foeglein A, Sun J, Dalton R M, Patel S, Howard W, Anderson E C, Barclay W S, Digard P J. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. Virology 2009, 83(16):8021-8031.
288. Wolstenholme A J, Barrett T, Nichol S T, Mahy B W. Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. J Virol 1980, 35: 1-7.
289. Wu Z, Earle J, Saito S, Anderson C W, Appella E, Xu Y. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol. Cell. Biol. 2002, 22: 2441-2449.
290. Wurzer W J, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 2003, 22: 2717-2718.
291. Wurzer W J, Ehrhardt C, Pleschka S, et al. NF-Kb dependent induction of TRAIL and Fas/FasL is crucial for efficient influenza virus propagation. J Biol. Chem. 2004, 279: 30931-30937.
292. Xiong Y, Hannon G J, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993, 366: 701-704.
293. Xirodimas D P, Saville M K, Bourdon J C, Hay R T, Lane D P. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 2004, 118: 83-97.
294. Yang Y, Ludwig R L, Jensen J P, Pierre S A, Medaglia M V, Davydov I V, Safiran Y J, Oberoi P, Kenten J H, Phillips A C, Weissman A M, Vousden K H. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005, 7: 547-559.
295. Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 2005, 331: 851-858.
296. Zamarin D, García-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 2005, 1: e4.
297. Zamarin D, Ortigoza M B, Palese P. Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 2006, 80: 7976-7983.
298. Zhan Q, Antinore M J, Wang X W, Carrier F, Smith M L, Harris C C, Fornace A J. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 1999, 18: 2892-2900.
299. Zhang J, Leser GP, Pekosz A, Lamb RA. The cytoplasmic tails of the influenza virus spike glycoproteins are required for normal genome packaging. Virology 2000, 269(2): 325-34.
300. Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998, 92(6):725-34
301. Zhang Y, Wolf G W, Bhat K, Jin A, Allio T, Burkhart W A, Xiong Y. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol. Cell. Biol. 2003, 23: 8902-8912.
302. Zhao W, Kruse J P, Tang Y, Jung S Y, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 2008, 451: 587–590.
303. Zhirnov O P. Isolation of matrix protein M1 from influenza viruses by acid-dependent extraction with nonionic detergent. Virology 1992, 186: 324-330
304. Zhirnov O P, Konakova T E, Wolff T, Klenk H D. 3NS1 protein of influenza A virus down-regulates apoptosis. J Virol 2002, 76: 1617-1625.
305. Zhu Q, Yang H, Chen W, Cao W, Zhong G, Jiao P, Deng G, Yu K, Yang C, Bu Z, Kawaoka Y, Chen H. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 2008, 82: 220-228.
2.沈阳.猪流感病毒感染细胞的p53蛋白变化及生物学活性分析[博士学位论文] .北京:中国农业科学院研究生院,2009.
3.殷震和刘景华.动物病毒学.1997, p:704-730.
4. Abida W M, Nikolaev A, Zhao W, Zhang W, Gu W. FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J. Biol. Chem. 2007, 282: 1797-1804.
5. Agustin P, Paul D. The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 2002, 83: 723-734.
6. Allison S J, Jiang M, Milner J. Oncogenic viral protein HPV E7 upregulates the SIRT1 longivity protein in human cervical cancer cells. Aging 2009, 1: 316-327.
7. An W, Kim J, Roeder R G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 2004, 117: 735-748.
8. Appella E, Anderson C W. Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 2001, 268: 2764-2772.
9. Aragon T, de la Luna S, Novoa I, Carrasco L, Ortin J, Nieto A. Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol Cell Biol 2000, 20: 6259-6268.
10. Arzt S, Petit I, Burmeister W P, Ruigrok R W, Baudin F. Structure of a knockout mutant of influenza virus M1 protein that has altered activities in membrane binding, oligomerisation and binding to NEP (NS2). Virus Res 2004, 99: 115-119.
11. Ashcroft M, Kubbutat M H, Vousden K H. Regulation of p53 function and stability by phosphorylation. Mol. Cell. Biol. 1999, 19: 1751-1758.
12. Ayed A, Mulder F A, Yi G S, Lu Y, Kay L E, Arrowsmith C H. Latent and active p53 are identical in conformation. Nat. Struct. Biol. 2001, 8: 756-760.
13. Bancroft C T, Parslow T G. Evidence for segment-nonspecific packaging of the influenza a viru genome. J Virol 2002, 76(14): 7133-7139.
14. Barboza J A, Iwakuma T, Terzian T, El-Naggar A K, Lozano G. Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol. Cancer Res. 2008, 6: 947-954.
15. Benjamin G H, Richard E R, Juan O, David J. The multifunctional NS1 protein of influenza A viruses. J Gen Virol 2008, 89: 2359-2376.
16. Bergamaschi D, Samuels Y, O’Neil N J, Trigiante G, Crook T, Hsieh J K, O’Connor D J, Zhong S, Campargue I, Tomlinson M L, Kuwabara P E, Lu X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 2003, 33: 162-167.
17. Berns K, Hijmans E M, Mullenders J, Brummelkamp T R, Velds A, Heimerikx M, Kerkhoven R M,Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley P S, Beijersbergen R L, Bernards R. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 2004, 428: 431-437.
18. Biswas S K, Nayak D P. Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol 1994, 68:1819-1826.
19. Blattner C, Tobiasch E, Litfen M, Rahmsdorf H J, Herrlich P. DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene 1999, 18: 1723- 1732.
20. Bornholdt Z A, Prasad B V. X-ray structure of influenza virus NS1 effector domain. Nat Struct Mol Biol 2006, 13: 559-560.
21. Bourdon J C, Renzing J, Robertson P L, Fernandes K N, Lane, D P. Scotin. a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J Cell Biol 2002, 158: 235-246,.
22. Brooks C L, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell Biol. 2003, 15: 164-171.
23. Brooks C L, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 2006, 21: 307-315.
24. Brummelkamp T R, Fabius A W, Mullenders J, Madiredjo M, Velds A, Kerkhoven R M, Bernards R, Beijersbergen R L. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nat. Chem. Biol. 2006, 2: 202-206.
25. Budanov A V, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008, 134: 451-460.
26. Bui M, Whittaker G, Helenius A. The effect of M1 protein and low pH on nuclear transport of influenza virus vRNPs. J Virol 1996, 70: 8391-8401.
27. Burgui, I, Aragon T, Ortin J, Nieto A. PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. J Gen Virol 2003, 84: 3263-3274.
28. Bussey K A, Bousse T L, Desmet E A, Kim B, Takimoto T. PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol. 2010,Feb 24.
29. Canman C E, Lim D S, Cimprich K A, Yaya Y, Tamai K, Sakaguchi K, Appella E, Kastan M Siliciano J D. Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53. Science 1998, 281: 1677-1679
30. Cain C, Miller S, Ahn J, Prives C. The N terminus of p53 regulates its dissociation from DNA. J. Biol. Chem. 2000, 275: 39944-39953.
31. Carter S, Bischof O, Dejean A, Vousden K H. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat. Cell Biol. 2007, 9: 428-435.
32. Castiglioni P, Hall D S, Jacovetty E L, Ingulli E, Zanetti M. Protection against influenza A virus by memory CD8 T cells requires reactivation by bone marrow-derived dendritic cells. J Immunol 2008, 180: 4956-4964.
33. Cauthen A N, Swayne D E, Sekellick M J, Marcus P I, Suarez D L. Amelioration of influenza virus pathogenesis in chickens attributed to the enhanced interferon-inducing capacity of a virus with atruncated NS1 gene. J Virol 2007, 81: 1838-1847.
34. Cawley S, Bekiranov S, Ng HH, Kapranov P, Sekinger EA, Kampa D, Piccolboni A, Sementchenko V, Cheng J, Williams AJ, Wheeler R, Wong B, Drenkow J, Yamanaka M, Patel S, Brubaker S, Tammana H, Helt G, Struhl K, Gingeras TR.Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 2004, 116, 499-509.
35. Cecconi F, Alvarez-Bolado G, Meyer B I, Roth K A, Gruss P. Apaf1(CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998, 94: 727-737.
36. Chan W M, Mak M C, Fung T K, Lau A, Siu W Y, Poon R Y. Ubiquitination of p53 at multiple sites in the DNA-binding domain. Mol. Cancer Res. 2006, 4: 15-25.
37. Chao C, Wu Z, Mazur S J, Borges H, Rossi M, Lin T, Wang J Y, Anderson C W, Appella E, Xu Y. Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. Mol. Cell.Biol. 2006, 26: 6859-6869.
38. Chen W, Calvo P A, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med. 2001, 7: 1306-1312.
39. Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005, 121: 1071-1083.
40. Chien C Y, Xu Y, Xiao R, Aramini J M, Sahasrabudhe P V, Krug R M, Montelione G T. Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. Biochemistry 2004, 43: 1950-1962.
41. Chipuk J E, Kuwana T, Bouchier-Hayes L, Droin N M, Newmeyer D D, Schuler M, Green D R. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004, 303: 1010-1014.
42. Cheung C Y, Poon L L, Lau A S, Luk W, Lau Y L, Shortridge K F, Gordon S, Guan Y, Peiris J S. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002, 360: 1831-1837.
43. Cho Y, Gorina S, Jeffrey P D, Pavletich N P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 1994, 265: 346-355.
44. Chuikov S, Kurash J K, Wilson J R, Xiao B, Justin N, Ivanov G S, McKinney K, Tempst P, Prives C, Gamblin S J, Barlev N A, Reinberg D. Regulation of p53 activity through lysine methylation. Nature 2004, 432: 353-360.
45. Coleman J Robert. The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages. Virology J 2007, 4: 9.
46. Colman P M, Varghese J N, Laver W G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983, 303(5912): 41-44.
47. Conenello G M, Zamarin D, Perrone L A, Tempey T, Palese P. A single mutation in the PB1-F2 of
H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PloS Pathog 2007, 3: 1414-1421.
48. Craig A L, Vojtesek B, Mikutowska J, Thompson A, Hupp T R, Burch L.Novel phosphorylation sites of human tumour suppressor protein p53 at Ser20 and Thr18 that disrupt the binding of mdm2 (mouse double minute 2) protein are modified in human cancers. Biochem. J 1999, 342: 133-141
49. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison P R, Gasco M, Garrone O, Crook T, Ryan K M. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006, 126: 121–134.
50. Cummins J M, Rago C, Kohli M, Kinzler K W, Lengauer C, Vogelstein B. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 2004, 428: 1 p following 486.
51. Dai M S, Zeng S X, Jin Y, Sun X X, David L, Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol. Cell. Biol. 2004, 24: 7654-7668.
52. Das S, Raj L, Zhao B, Bernstein A, Aaronson S A, Lee S W. Hzf, a key modulator of p53 mediated transcription, functions as a critical determinant of cell survival and death upon genotoxic stress. Cell 2007130, 624-637.
53. de la Luna S, Fortes P, Beloso A, Ortin J. Influenza virus NS1 protein enhances the rate of translation initiation of viral mRNAs. J Virol 1995, 69: 2427-2433.
54. de Jong M D, Simmons C P, Thanh T T, Hien V M, Smith G J D, Chau T N B, Hoang D M, Chau N V V, Khanh T H, Dong V C, Qui Ph T, Cam B V, HaD Q, Guan Y, Peiris J S M, Chinh N T, Hien T T, Farrar J. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Medicine 2006, 12: 1203-1207.
55. Digard P, Elton D, Bishop K, Medcalf E, Weeds, A, Pope B. Modulation of nuclear localization of the infuenza virus nucleoprotein through interaction with actin filaments. J Virol 1999, 73: 2222- 2231.
56. Donelan N R, Basler C F, Garcia-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol 2003, 77: 13257-13266.
57. Dornan D, Wertz I, Shimizu H, Arnott D, Frantz G D, Dowd P, O’Rourke K, Koeppen H, Dixit V M. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004, 429: 86-92.
58. Eckardt-Michel J, Lorek M, Baxmann D. The fusion protein of respiratory syncytial virus triggers p53-dependent apoptosis. J virol 2008, 82(7): 3236-3249.
59. Ehrhardt C, Wolff T, Pleschka S, Planz O, Beermann W, Bode J G, Schmolke M, Ludwig S. Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses. J Virol 2007, 4: 3058-3067
60. Ekiert D C, Bhabha G, Elsliger M A, Friesen R H, Jongeneelen M, Throsby M, Goudsmit J, Wilson I A. Antibody recognition of a highly conserved influenza virus epitope. Science 2009, 324(5924): 246-51.
61. Elmore L W, Chang S F, Wang X W, Chang S,Callahan C P, Geller D A, Will H, Harris C C, Hancock A R. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl. Acad. Sci. U S A.1997, 94: 14707-14712.
62. Enami K, Sato T A, Nakada S, Enami M. Influenza virus NS1 protein stimulates translation of the M1 protein. J Virol 1994, 68: 1432-1437.
63. Enami M, Enami K. Characterization of influenza virus NS1 protein by using a novel helper-virus-free reverse genetic system. J Virol 2000, 74: 5556-5561.
64. Falcon A M, Fortes P, Marion R M, Beloso A, Ortin J. Interaction of influenza virus NS1 protein and the human homologue of Staufen in vivo and in vitro. Nucleic Acids Res 1999, 27: 2241–2247.
65. Fang S, Jensen J P, Ludwig R L, Vousden K H, Weissman A M. Mdm2 is a RING finger- dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 2000, 275: 8945-8951.
66. Feng L, Lin T, Uranishi H, Gu W, Xu Y. Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol. Cell. Biol. 2005, 25: 5389-5395.
67. Fernandez-Sesma A, Marukian S, Ebersole B J, Kaminski D, Park M S, Yuen T, Sealfon S C, Garcia-Sastre A, Moran T M. Influenza virus evades innate and adaptive immunity via the NS1 protein. J Virol 2006, 80: 6295-6304.
68. Flatt P M, Polyak K, Tang L J, Scatena C D, Westfall MD, Rubinstein LA, Yu J, Kinzler KW, Vogelstein B, Hill DE, Pietenpol JA. p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest. Cancer Lett 2000, 156: 63-72.
69. Fortes P, Beloso A, Ortin J. Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport. EMBO J 1994, 13, 704-712.
70. Gabriel G, Herwig A, Klenk H D. Interaction of polymerase subunit PB2 and NP with importin a1 is a determinant of host range of influenza A virus. PLoS Pathog 2008, 4, e11.
71. Gabriele N, Takeshi N., Yoshihiro K. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 2009, 459: 931-939.
72. Gack M U, Albrecht R A, Urano T, Inn K S, Huang I C, Carnero E, Farzan M, Inoue S, Jung J U, García-Sastre A. Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I. Cell Host Microbe 2009, 5(5): 439-49.
73. Gambotto A, Barratt-Boyes S M, de Jong M D, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet 2008, 371(9622):1464-75.
74. Garaigorta U, Ortin J. Mutation analysis of a recombinant NS replicon shows that influenza virus NS1 protein blocks the splicing and nucleo-cytoplasmic transport of its own viral mRNA. Nucleic Acids Res 2007, 35: 4573-4582.
75. Garcia-Cao I, Garcia-Cao M, Martin-Caballero M, Criado L M, Klatt P, Flores J M, Weill J, Blasco M A, Serrano M. "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 2002, 21: 6225-6235.
76. Garcia M A, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M. Impact of protein kinasePKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 2006, 70: 1032-1060.
77. Geiss G K, Salvatore M, Tumpey T M, Carter V S, Wang X, Basler C F Taubenberger J K. Bumgarner R E, Palese P, Katze M G, García-Sastre A. Cellular transcriptional profiling in influenza A virus infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A. 2002, 99: 1073641.
78. Gharbi S I, Zvelebil M J, Shuttleworth S J, Hancox T, Saghir N, Timms J F, Waterfield M D. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007, 404: 15-21.
79. Gibbs J S, Malide D, Hornung F, Bennink J R, Yewdell J W. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol 2003, 77, 7214-7224.
80. Goodman R H, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000, 14: 1553-1577.
81. Green D R, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009, 458(7242):1127-30.
82. Grossman S R, Deato M E, Brignone C, Chan H M, Kung A L, Tagami H, Nakatani Y, Livingston D M. Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300. Science 2003, 300: 342-344.
83. Groskreutz D J, Monick M M, Yarovinsky T O, Powers L S, Quelle D E, Varga S M, Look D C, Hunninghake G W. Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells. J Immunol 2007, 179: 2741-2747.
84. Gu W, Roeder R G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997, 90: 595-606.
85. Guo Z, Chen L M, Zeng H, Gomez J A, Plowden J, Fujita T, Katz J M, Donis R O, Sambhara S. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am J Respir Cell Mol Biol 2007, 36: 263-269.
86. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv. Cancer Res. 2000, 77: 81-137.
87. Hale B G, Jackson D, Chen Y H, Lamb R A, Randall R E. Influenza A virus NS1 protein binds p85b and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad Sci U S A 2006, 103: 14194 -14199.
88. Hale B G, Barclay W S, Randall R E, Russell R J.Structure of an avian influenza A virus NS1 protein effector domain. Virology 2008a, 378: 1-5.
89. Hale B G, Batty I H, Downes C P, Randall R E.Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation. J. Biol. Chem. 2008b, 283:1372-1380.
90. Hale B G, Randall R E, Ort?′n J, Jackson D. The multifunctional NS1 protein of influenza viruses. Journal of General Virology 2008c, 89: 2359-2376
91. Harris C C. p53 Tumor suppressor gene: from the basic research laboratory to the clinic– an abridged historical perspective. Carcinogenesis 1996, 17: 1187-1198.
92. Hatada E, Hasegawa M, Shimizu K, Hatanaka M, Fukuda R. Analysis of influenza A virus temperature-sensitive mutants with mutations in RNA segment 8. J Gen Virol 1990, 71: 1283-1292.
93. Hatada E, Saito S, Fukuda R. Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells. J Virol 1999, 73: 2425-2433.
94. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997, 387: 296-299.
95. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci 2003, 116: 4077-4085.
96. Hayman A, Comely S, Lackenby A, Murphy S, McCauley J, Goodbourn S, Barclay W. Variation in the ability of human influenza A viruses to induce and inhibit the IFN-βpathway. Virology 2006, 347: 52-64.
97. Hayman A, Comely S, Lackenby A, Hartgroves L C, Goodbourn S, McCauley J W, Barclay W S. NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response. J Virol 2007, 81: 2318-2327.
98. Heikkinen L S, Kazlauskas A, Melen K, Wagner R, Ziegler T, Julkunen I, Saksela K. Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. J. Biol. Chem. 2008, 283: 5719-5727.
99. Hermeking H, Lengauer C, Polyak K, He T C, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B.
14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997, 1: 3-11.
100. Hoffmann E, Stech J, Guan Y, Webster R G, Perez D R. Universal primer set for the full-length amplification of all influenza viruses. Arch. Virol. 2001, 146: 2275-2289.
101. Holowaty M N, Frappier L. HAUSP/USP7 as an Epstein–Barr virus target. Biochemical Society Transactions 2004, 32(5): 731-734.
102. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997, 420: 25-27.
103. Honda R, Yasuda H. Association of p19 (ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999, 18: 22-27.
104. Huang J, Perez-Burgos L, Placek B J, Sengupta R, Richter M, Dorsey J A, Kubicek S, Opravil S, Jenuwein T, Berger S L. Repression of p53 activity by Smyd2-mediated methylation. Nature 2006, 444: 629-632.
105. Huang J, Sengupta R, Espejo A B, Lee M G, Dorsey J A, Richter M, Opravil S, Shiekhattar R, Bedford M T, Jenuwein T, Berger S L. p53 is regulated by the lysine demethylase LSD1. Nature 2007, 449: 105-108.
106. Hyland L, Webby R, Sandbulte M R, Clarke B, Hou S. Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model. Virology 2006, 349: 156-163.
107. Itahana K, Mao H, Jin A, Itahana Y, Clegg H V, Lindstrom M S, Bhat K P, Godfrey V L, Evan G I,Zhang Y. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 2007, 12: 355-366.
108. Itoh M, Hotta H. Structure, function and regulation of expression of influenza virus matrix M1 protein. Nippon. Rinsho 1997, 55(10): 2581-2586.
109. Ito A, Lai C H, Zhao X, Saito S, Hamilton M H, Appella E, and Yao T P. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 2001, 20: 1331-1340.
110. Iwakuma T, Lozano G. Crippling p53 activities via knock-in mutations in mouse models. Oncogene 2007, 26: 2177-2184.
111. Iyer N G, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene 2004, 23: 4225-4231.
112. Jackson D, Hossain M J, Hickman D, Perez D R, Lamb R A. A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc Natl Acad Sci U S A 2008, 105: 4381-4386.
113. Jansson M, Durant S T, Cho E C, Sheahan S, Edelmann M, Kessler B, La Thangue N B. Arginine methylation regulates the p53 response. Nat. Cell Biol. 2008, 10: 1431-1439.
114. Jenuwein T, Allis C D. Translating the histone code. Science. 2001, 293: 1074-1080.
115. Jiao P, Tian G, Li Y, Deng G, Jiang Y, Liu C, Liu W, Bu Z, Kawaoka Y, Chen H. A single-amino- acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 2008, 82: 1146-1154.
116. Johnson T M, Hammond E M, Giaccia A, Attardi L D. The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality. Nat. Genet. 2005, 37: 145-152.
117. Jones S N, Roe A E, Donehower L A, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 1995, 378: 206-208.
118. Kaeser M D, Iggo R D. Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl. Acad. Sci. U S A 2002, 99: 95-100.
119. Kemler I, Whittaker G, Helenius A. Nuclear import of microinjected influenza virus ribonucleoproteins. Virology 1994, 202: 1028-1033,
120. Kern S E, Kinzler K W, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequence-specific DNA binding protein. Science 1991, 252: 1708-1711.
121. Kim E, Rohaly G, Heinrichs S, Gimnopoulos D, Meissner H, Deppert W. Influence of promoter DNA topology on sequence-specific DNA binding and transactivation by tumor suppressor p53. Oncogene 1999, 18: 7310-7318.
122. Kim J E, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008, 451: 583-586.
123. Knights C D, Catania J, Di Giovanni S, Muratoglu S, Perez R, Swartzbeck A, Quong A A, Zhang X, Beerman T, Pestell R G, Avantaggiati M L. Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. J. Cell Biol. 2006, 173: 533-544.
124. Kochs G, Garcia-Sastre A, Martinez-Sobrido L. Multiple anti-interferon actions of the influenza Avirus NS1 protein. J Virol 2007a, 81: 7011-7021.
125. Kochs G, Koerner I, Thiel L, Kothlow S, Kaspers B, Ruggli N, Summerfield A, Pavlovic J, Stech J, Staeheli P. Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J Gen Virol 2007b, 88: 1403-1409.
126. Kok K H, Jin D Y. Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells. J Gen Virol 2006, 87: 2639-2644.
127. Krug R M, Yuan W, Noah D L, Latham A G. Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein. Virology 2003, 309:181-189.
128. Krummel K A, Lee C J, Toledo F, Wahl G M. The C-terminal lysines fine-tune P53 stress responses in a mouse model but are not required for stability control or transactivation. Proc. Natl. Acad. Sci. U S A 2005, 102: 10188-10193.
129. Kruse J P, Gu W. MSL2 promotes MDM2 independent cytoplasmic localization of p53. J. Biol. Chem. 2008a 284, 3250-3263.
130. Kruse J P, Gu W. SnapShot: p53 posttranslational modifications. Cell 2008b, 133: 930.
131. Kruse J P, Gu W. Modes in p53 regulation. Cell 2009, 137: 609-622.
132. Kubbutat M H, Jones S N, Vousden K H. Regulation of p53 stability by Mdm2. Nature 1997, 387: 299-303.
133. Kurokawa M, Koyama A H, Yasuoka, S, Adachi AInfluenza virus overcomes apoptosis by rapid multiplication. Int J Mol Med 1999, 3: 527-530.
134. Lain S, Hollick J J, Campbell J, Staples O D, Higgins M, Aoubala M, McCarthy A, Appleyard V, Murray KE, Baker L, Thompson A, Mathers J, Holland S J, Stark M J, Pass G, Woods J, Lane D P, Westwood N J. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008, 13: 454-463.
135. Lamb R A, Takeda M. Death by influenza virus protein. Nat Med. 2001, 7(12):1306-12.
136. Laptenko O, Prives C. Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ. 2006, 13: 951-961.
137. Leng R P, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant J M, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003, 112: 779-791.
138. Leu J I, Dumont P, Hafey M, Murphy M E, George D L. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol. 2004, 6: 443-450.
139. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008, 132: 27-42.
140. Licheng S, Summers D F, Peng Q, Galarza J M. Influenza A virus polymerase subunit PB2 is the endonuclease which cleaves host cell mRNA and functions only as the trimeric enzyme. Virology 1995, 208: 38-47.
141. Li L, Guo L, Tao Y, , Zhou S, Wang Z, Luo W, Hu D, Li Z, Xiao L, Tang M, Yi W, Tsao S W, Cao Y. Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases. Cancer Letters 2007, 255 (2): 219-231.
142. Li M, Chen D, Shiloh A, Luo J, Nikolaev A Y, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002a, 416: 648-653.
143. Li M, Luo J, Brooks C L, Gu W. Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem. 2002b, 277: 50607-50611.
144. Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol. Cell 2004, 13: 879-886.
145. Li S, Min J Y, Krug R M, Sen G C. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 2006, 349: 13-21
146. Li X, Qiu Y, Shen Y, Ding C, Liu P, Zhou J, Ma Z. Splicing together different regions of a gene by modified polymerase chain reaction-based site-directed mutagenesis. Anal Biochem. 2008, 373(2):398-400.
147. Li Y, Anderson D H, Liu Q, Zhou Y. Mechanism of influenza A virus NS1 protein interaction with the p85β, but not the p85α, subunit of PI3K and up-regulation of PI3K activity. J. Biol. Chem. 2008, 283: 23397-23409.
148. Li Z, Jiang Y, Jiao P, Wang A, Zhao F, Tian G, Wang X, Yu K, Bu Z, Chen H. The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J Virol 2006, 80: 11115-11123.
149. Linares L K, Hengstermann A, Ciechanover A, Muller S, Scheffner M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl. Acad. Sci. U S A 2003, 100: 12009-12014.
150. Ling Bai, Wei-Guo Zhu. p53: Structure, Function and Therapeutic Applications. Journal of Cancer Molecules 2006, 2(4): 141-153,
151. Lipatov A S, Andreansky S, Webby R J, Hulse D J, Rehg J E, Krauss S, Perez D R, Doherty P C, Webster R G, Sangster M Y. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol 2005, 86: 1121- 1130.
152. Liu X, Yue P, Khuri F R, Sun S Y. p53 upregulates death receptor 4 expression through an intronic p53 binding site. Cancer Res 2004, 64: 5078-5083.
153. Liu L, Scolnick D M, Trievel R C, Zhang H B, Marmorstein R, Halazonetis T D, Berger S L. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol. Cell. Biol. 1999, 19: 1202-1209.
154. Liu Y, Lagowski J P, Vanderbeek G E, Kulesz-Martin M F. Facilitated search for specific genomic targets by p53 C-terminal basic DNA binding domain. Cancer Biol. Ther. 2004, 3: 1102-1108.
155. Llanos S, Clark P A, Rowe J, Peters G. Stabilization of p53 by p14 (ARF) without relocation of MDM2 to the nucleolus. Nat. Cell Biol. 2001, 3: 445-452.
156. Lohrum M A, Woods D B, Ludwig R L, Balint E, Vousden K H. C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell. Biol. 2001, 21: 8521-8532.
157. Lohrum M A, Ludwig R L, Kubbutat M H, Hanlon M, Vousden K H. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 2003, 3: 577-587.
158. Long J X, Peng D X, Liu Y L, Wu Y T, Liu X F. Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. Virus Genes 2008, 36: 471-478.
159. Lowe S W, Sherr C J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr. Opin. Genet. Dev. 2003, 13: 77-83.
160. Lu X, Ma O, Nguyen T A, Jones S N, Oren M, Donehower L A. The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 2007, 12: 342-354.
161. Ludwig S, Wang W, Ehrhardt C, Zheng H, Donelan N, Planz O, Pleschka S, García-Sastre A, Heins G, Wolff T. The influenza A virus NS1 protein inhibits activation of the jun N-terminal kinase and AP-1 transcription factors. J Virol 2002, 76: 11166-11171.
162. Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000, 408: 377-381.
163. Luo J, Nikolaev A Y, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001, 107: 137-148.
164. Marchenko N D, Moll U M. The role of ubiquitination in the direct mitochondrial death program of p53. Cell Cycle 2007a, 6: 1718-1723.
165. Marchenko N D, Wolff S, Erster S, Becker K, Moll U M. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 2007b, 26: 923-934.
166. Marion R M, Aragon T, Beloso A, Nieto A, Ortin J. The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res 1997a, 25: 4271-4277.
167. Marion R M, Zurcher T, de la Luna S, Ortin J. Influenza virus NS1 protein interacts with viral transcription-replication complexes in vivo. J Gen Virol 1997b, 78: 2447-2451.
168. Marine J C, Jochemsen A G. Mdmx as an essential regulator of p53 activity. Biochem. Biophys. Res. Commun. 2005, 331: 750-760.
169. Marine J C, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006, 13: 927-934.
170. Martin K, Helenius A. Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell 1991, 67: 117-130.
171. Massin P, van der Werf S, Naffakh N. Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol 2001, 75(11):5398-404.
172. Matrosovich M N, Matrosovich T Y, Gray T, Roberts N A, Klenk H D.Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 2004, 78 (22): 12665-7.
173. Matskevich A A, Moelling K. Dicer is involved in protection against influenza A virus infection. J Gen Virol 2007, 88: 2627-2635.
174. Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H. p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 2002, 62: 2883-2889.
175. Mayo L D, Donner D B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. TrendsBiochem. Sci. 2002, 27: 462-467.
176. McAuley J L, Hornung F, Boyd K L, Smith A M, McKeon R, Bennink J, Yewdell J W,McCullers J A. Expression of the 1918 Influenza A Virus PB1-F2 Enhances the Pathogenesis of Viral and Secondary Bacterial Pneumonia. Cell Host Microbe 2007, 2:240-249.
177. Meek D W. The p53 response to DNA damage. DNA Repair (Amst.) 2004, 3: 1049-1056.
178. Melchior F, Hengst L. SUMO-1 and p53. Cell Cycle 2002, 1: 245-249.
179. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen A G. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 2005, 4: 1166-1170.
180. Melen K, Kinnunen L, Fagerlund R, Ikonen N, Twu K Y, Krug R M, Julkunen I. Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes. J Virol 2007, 81: 5995-6006.
181. Mibayashi M, Martinez-Sobrido L, Loo Y M, Cardenas W B, Gale M Jr, Garcia-Sastre A. Inhibition of retinoic acidinducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 2007, 81: 514-524.
182. Michael D, Oren M. The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol. 2003, 13: 49-58.
183. Migliorini D, Denchi E L, Danovi D, Jochemsen A, Capillo, M, Gobbi A, Helin K, Pelicci P G, Marine J C. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol. Cell. Biol. 2002, 22: 5527-5538.
184. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll U M. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 2003, 11: 577-590.
185. Min J Y, Krug R M. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2’-5’oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A, 2006, 103: 7100-7105.
186. Min J Y, Li S, Sen, G C, Krug R M. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 2007, 363, 236-243.
187. Minsky N, Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol. Cell 2004, 16: 631-639.
188. Montes de Oca Luna R., Wagner D S, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 1995, 378: 203-206.
189. Morris S J, Price G E, Barnett J M, Hiscox S A, Smith H, Sweet C. Role of neuraminidase in influenza virus-induced apoptosis. J Gen. Virol. 1999, 80: 137-146.
190. Munoz-Fontela C, Garcia MA, Garcia-Cao I, Collado M, Arroyo J, Esteban M, Serrano M, Rivas C. Resistance to viral infection of super p53 mice. Oncogene 2005, 24: 3059-3062.
191. Nakano K, Vousden K H. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001, 7: 683-694.
192. Narayanan K, Chen C J, Maeda J, Makino S. Nucleocapsid-independent specific viral RNApackaging via viral envelope protein and viral RNA signal. J Virol 2003, 77(5): 2922-7.
193. Neumann G, Brownlee G G, Fodor E, Kawaoka Y. Orthomyxovirus replication, transcription, and polyadenylation. Curr Top Microbiol Immunol. 2004, 283: 121-43.
194. Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 2009, 459: 931-939.
195. Nicole C R, Matt S, Frank T V, Ervin F. NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol 2009, 90: 1398-1407.
196. Noah D L, Twu K Y, Krug R M. Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 39 end processing of cellular pre-mRNAS. Virology 2003, 307: 386-395.
197. Obenauer J C, Denson J, Mehta P K, Su X, Mukatira S, Finkelstein D B, Xu X, Wang J, Ma J, Fan Y, Rakestraw Y M, Webster R G, Hoffmann E, Krauss S, Zheng J, Zhang Z, Naeve C W. Large- scale sequence analysis of avian influenza isolates. Science 2006, 311: 1576-1580.
198. O'Connor L, Harris A W, Strasser A. CD95 (Fas/APO-1) and p53 signal apoptosis independently in diverse cell types. Cancer Res 2000, 60: 1217-1220.
199. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000, 288: 1053-1058.
200. Ohkubo S, Tanaka T, Taya Y, Kitazato K, Prives C. Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription. J. Biol. Chem. 2006, 281: 16943–16950.
201. Oleg P Z, Hans-Dieter K. Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis 2007, 12: 1419-1432.
202. O’Neill R E, Jaskunas R, Blobel G, Palese P, Moroianu J. Nuclear import of infuenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. J. Biol. Chem. 1995, 270: 22701-22704.
203. O’Neill R E, Talon J, Palese P. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 1998, 17: 288-296.
204. Opitz B, Rejaibi A, Dauber B, Eckhard J, Vinzing M, Schmeck B, Hippenstiel S, Suttorp N, Wolff T. IFN-βinduction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 2007, 9: 930-938.
205. Oren M, Rotter, V. Introduction: p53–the first twenty years. Cell. Mol. Life Sci. 1999, 55: 9-11.
206. Oren M. Decision making by p53: life, death and cancer. Cell Death Differ 2003, 10: 431-442.
207. Palese P, Shaw M L. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams &Wilkins; 2007.
208. Parant J, Chavez-Reyes A, Little N A, Yan W, Reinke V, Jochemsen A G, Lozano G. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat. Genet. 2001, 29: 92-95.
209. Park Y W, Katze M G. Translational control by influenza virus. Identification of cis-actingsequences and trans-acting factors which may regulate selective viral mRNA translation. J. Biol. Chem. 1995, 270: 28433-28439.
210. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi P P, Pelicci P G. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000, 406, 207-210.
211. Pichlmair A, Schulz O, Tan C P, Naslund T I, Liljestrom P, Weber F, Reis e Sousa C. RIG-I- mediated antiviral responses to single-stranded RNA bearing 59-phosphates. Science 2006, 314: 997-1001.
212. Portela A and Digard P. The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 2002, 83: 723-734.
213. Poyurovsky M V, Priest C, Kentsis A, Borden K L, Pan Z Q, Pavletich N, Prives C. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 2007, 26: 90-101.
214. Qiu Y, Krug R M. The influenza virus NS1 protein is a poly(A)-binding protein that inhibits nuclear export of mRNAs containing poly(A). J Virol 1994, 68: 2425-2432.
215. Quinlivan M, Zamarin D, Garcia-Sastre A, Cullinane A, Chambers T, Palese P. Attenuation of equine influenza viruses through truncations of the NS1 protein. J Virol 2005, 79: 8431-8439.
216. Randall R E, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008, 89: 1-47.
217. Ringshausen I, O’Shea C C, Finch A J, Swigart L B, Evan G I. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006, 10: 501-514.
218. Rivas C, Aaronson S A, Munoz-Fontela C. Dual role of p53 in innate antiviral immunity. Viruses 2010, 2: 298-313.
219. Roth J, Dobbelstein M, Freedman D A, Shenk T, Levine A J. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 1998, 17: 554-564.
220. Sakaguchi K, Herrera J E, Saito S, Miki T, Bustin M, Vassilev A, Anderson C W, and Appella E. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 1998, 12: 2831-2841.
221. Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson C W, Appella E. Damage-mediated phosphorylation of human p53threonine 18 through a cascade mediated by a casein 1-like kinase effect on Mdm2 binding. J. Biol. Chem. 2000, 275: 9278-9283.
222. Salomon R, Franks J, Govorkova EA, Ilyushina N A., Yen H L, Hulse-Post D J, Humberd J, Trichet M, Rehg J E., Webby R J., Webster R G, Hoffmann E. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 2006, 203: 689-697.
223. Salvatore, M., Basler, C. F., Parisien, J. P., Horvath, C. M., Bourmakina, S., Zheng, H., Muster, T., Palese, P. & Garcia-Sastre, A. Effects of influenza A virus NS1 protein on protein expression: theNS1 protein enhances translation and is not required for shutoff of host protein synthesis. J Virol 2002, 76: 1206-1212.
224. Samuels-Lev Y, O’Connor D J, Bergamaschi D, Trigiante G, Hsieh J K, Zhong S, Campargue I, Naumovski L, Crook T, and Lu X. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 2001, 8: 781-794.
225. Sanz-Ezquerro J J, Zurcher T, de la Luna S, Ortin J, and Nieto A. The amino-terminal one-third of the influenza virus PA protein is responsible or the induction of proteolysis. J Virol 1996, 70: 1905 -1911.
226. Sarah L N, Elizabeth M, Dawn F, Anne E M, Debra E Paul D. Identification of the domains of the influenza A virus M1 matrix protein required for NP binding, oligomerization and incorporation into virions. J Gen Virol 2007, 88: 2280-2290.
227. Satterly N, Tsai P L, van Deursen J, Nussenzveig D R, Wang Y, Faria P A, Levay A, Levy D E, Fontoura B M. Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc Natl Acad Sci U S A 2007, 104: 1853-1858.
228. Scheffner M, Huibregtse J M, Vierstra R D, Howley P M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993, 75, 495-505.
229. Schon O, Friedler A, Bycroft M, Freund S M, Fersht, A R. Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 2002, 323(3): 491-501.
230. Shangary S, Qin D, McEachern D, Liu M, Miller R S, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah R B, Pienta K J, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl. Acad. Sci. U S A 2008, 105: 3933-3938.
231. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol. 2009, 49: 223-241.
232. Shapira S D, Gat-Viks I, Shum B O, Dricot A, de Grace M M, Wu L, Gupta P B, Hao T, Silver S J, Root D E, Hill D E, Regev A, Hacohen N. A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection. Cell 2009, 139(7):1255-67.
233. Shen Y, Wang X, Guo L, Qiu Y, Li X, Yu H, Xiang H, Tong G, Ma Z. Influenza A virus induces p53 accumulation in a biphasic pattern. Biochem Biophys Res Commun. 2009, 382(2): 331-335.
234. Sherr C J. Divorcing ARF and p53: an unsettled case. Nat. Rev. Cancer 2006, 6: 663-673.
235. Shi X, Kachirskaia I, Yamaguchi H, West L E, Wen H, Wang E W, Dutta S, Appella E, Gozani O. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 2007, 27: 636-646.
236. Shieh S Y, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1997, 91: 325-334.
237. Shieh S Y, Ahn J, Tamai K, Taya Y, Prives C. The human homologs of checkpoint kinases Chk1and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 2000, 14: 289-300.
238. Shin Y K, Liu Q, Tikoo S K, Babiuk L A , Zhou Y. Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 2007a, 88: 13-18.
239. Shin Y K, Li Y, Liu Q, Anderson D H, Babiuk L A, Zhou Y. SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signalling pathway activation. J Virol 2007b, 81: 12730-12739.
240. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006, 440(7083): 435-436.
241. Sieczkarski S B, Whittaker G R. Viral entry. Curr Top Microbiol Immunol. 2005, 285:1–23.
242. Silverman R H. Viral encounters with 2’,5’-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 2007, 81: 12720-12729.
243. Solorzano A, Webby R J, Lager K M, Janke B H, Garcia-Sastre A, Richt J A. Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs. J Virol 2005, 79: 7535-7543.
244. Song M S, Song S J, Kim S Y, Oh H J, Lim D S. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J 2008, 27: 1863-1874.
245. Stegmann T. Membrane fusion mechanisms: the influenza hemagglutinin paradigm and its implications for intracellular fusion. Traffic 2000, 1(8): 598-604。
246. Stevens J, Corper A L, Basler C F, Taubenberger J K, Palese P, Wilson I A. Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus. Science 2004, 33:1866-1870.
247. Stommel J M, Wahl G M. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J 2004, 23: 1547-1556.
248. Sui G, Affar El B, Shi Y, Brignone C, Wall N R, Yin P, Donohoe M, Luke M P, Calvo D, Grossman S R. Yin Yang 1 is a negative regulator of p53. Cell 2004, 117: 859-872.
249. Susana G, Thomas Z, Juan O. Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: a model for the viral RNA polymerase structure. Nucleic Acids Research 1996, 24(22): 4456-4463.
250. Sykes S M, Mellert H S, Holbert M A, Li K, Marmorstein R, Lane W S, McMahon S B. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 2006, 24: 841-851.
251. Szak, S.T., Mays, D., and Pietenpol, J.A. Kinetics of p53 binding to promoter sites in vivo. Mol. Cell. Biol. 2001, 21: 3375-3386.
252. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, Shibue T, Honda K, Taniguchi T. Integration of interferon-α/βsignaling to p53 responses in tumoursuppression and antiviral defence. Nature 2003, 424: 516-523.
253. Takimoto R, El-Deiry W S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNAbinding site. Oncogene 2000, 19: 1735-1743.
254. Talon J, Horvath C M, Polley R, Basler C F, Muster T, Palese P, Garcia-Sastre A. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 2000a, 74: 7989-7996.
255. Wang X, Li M, Zheng H, Muster T, Palese P, Beg A A, Garcia-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kB and induction of alpha/beta interferon. J Virol 2000, 74: 11566-11573.
256. Tanaka T, Ohkubo S, Tatsuno I, Prives C. hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. Cell 2007, 130: 638-650.
257. Tang J, Qu L K, Zhang J, Wang W, Michaelson J S, Degenhardt Y Y, El-Deiry W S, Yang X. Critical role for Daxx in regulating Mdm2. Nat. Cell Biol. 2006a, 8: 855-862.
258. Tang Y, Luo J, Zhang W, and Gu W. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 2006b, 24: 827-839.
259. Tang, Y., Zhao, W., Chen, Y., Zhao, Y., and Gu, W. Acetylation is indispensable for p53 activation. Cell 2008, 133: 612-626.
260. Tarendeau F, Crepin T, Guilligay D, Ruigrok W H, Cusack S, Hart D J. Host determinant residue lysine 627 lies on the surface of a discrete, folded domain of influenza virus polymerase PB2 subunit. PLoS Pathog. 2008, 4, e1000136.
261. Tasdemir E, Maiuri MC , Galluzzi L, Vitale I , Djavaheri-Mergny M, D'Amelio M, Criollo A , Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio J M, Carnuccio R, Moll U M, Madeo F, Paterlini-Brechot P , Rizzuto R, Szabadkai G, Pierron R, Blomgren K , Tavernarakis N, Codogno P , Cecconi F, Kroemer G. Regulation of autophagy by cytoplasmic p53. Nature Cell Biol. 2008, 10: 676-687.
262. Teufel D P, Bycroft M, Fersht A R. Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2. Oncogene 2009, 28(20): 2112-2118.
263. Thornborrow E C, Patel S, Mastropietro A E, Schwartzfarb E M, Manfredi J J. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 2002, 21: 990-999.
264. Tian C, Xing G, Xie P, Lu K, Nie J, Wang J, Li L, Gao M, Zhang L, He F. KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nat. Cell Biol. 2009, 11: 580-591.
265. Timofeeva T A, Klenk H D, Zhirnov O P. Identification of the protease-binding domain in the N-terminal region of influenza virus A matrix protein M1. Mol. Biol. 2001, 35: 411-416.
266. Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C, Pan H, Kessler H, Pancoska P, Moll UM. WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J. Biol. Chem. 2006, 281: 8600-8606.
267. Trigiante G, and Lu X. ASPP [corrected] and cancer. Nat. Rev. Cancer 2006, 6: 217–226.
268. Tumpey T M, Garc?′a-Sastre A, TaubenbergerJ K, Palese P, Swayne D E, Basler C F. Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. U S A 2004, 101: 3166-3171
269. Tumpey T M, Basler C F, Aguilar P V, Zeng H, Solórzano A, Swayne D E, Cox N J, Katz J M, Taubenberger J K, Palese P, García-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005, 310:77-80.
270. Turpin E, Luke K, Jones J, Tumpey T, Konan K, Schultz-Cherry S. Influenza virus infection increases p53 activity: role of p53 in cell death and viral replication. J Virol 2005, 7: 8802-8811.
271. Twu K Y, Noah D L, Rao P, Kuo R L, Krug R M. The CPSF30 binding site on the NS1A protein of influenza A virus s a potential antiviral target. J Virol 2006, 80: 3957-3965.
272. Twu K Y, Kuo R L, Marklund J, Krug R M. The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol 2007, 81: 8112-8121.
273. Uldrijan S, Pannekoek W J, Vousden K H. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J 2007, 26: 102-112.
274. Van Hoeven N, Pappas C, Belsera J A., Maines T R., Zeng H, García-Sastre A, Sasisekharan R, Katz J M, Tumpey T M. Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proc. Natl Acad. Sci. U S A 2009, 106:3366-3371.
275. van Riel D, Munster V J, de Wit E, Rimmelzwaan G F, Fouchier R A, Osterhaus A D, Kuiken T. H5N1 virus attachment to lower respiratory tract. Science 2006, 312: 399
276. Vassilev L T, Vu B T, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303: 844-848.
277. Vaziri H, Dessain S K, Ng Eaton E, Imai S I, Frye R A, Pandita T K, Guarente L, Weinberg R A. hSIR2(SIRT1) functions as an NADdependent p53 deacetylase. Cell 2001, 107:149-159.
278. Vogelstein B, Lane D, Levine A J. Surfing the p53 network. Nature 2000,408: 307-310.
279. Wahl G M. Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo. Cell Death Differ. 2006, 13: 973-983.
280. Wang TT, Palese P. Unraveling the mystery of swine influenza virus. Cell, 2009, 137: 983-985.
281. Wang X, Basler C F, Williams B R., Silverman R H, Palese P, Garcia-Sastre A. Functional replacement of the carboxyterminal two-thirds of the influenza A virus NS1 protein with short heterologous dimerization domains. J Virol 2002, 76:12951-12962.
282. Wang X, Taplick J, Geva N, Oren M. Inhibition of p53 degradation by Mdm2 acetylation. FEBS Lett. 2004, 56: 195-201.
283. Watanabe T, Watanabe S, Shinya K, Kim J H, Hatta M, Kawaoka Y. Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. Proc Natl Acad Sci U S A. 2009, 106(2):588-92.
284. Weber J D, Taylor L J, Roussel M F, Sherr C J, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 andactivates p53. Nat. Cell Biol. 1999, 1: 20-26.
285. Whittaker G R. Intracellular trafficking of influenza virus: clinical implications for molecular medicine. Expert Rev Mol Med. 2001, 1: 1-13.
286. Wilson I A, Skehel J J, Wiley D C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3? resolution. Nature 1981, 289(5796):366-373.
287. Wise H M, Foeglein A, Sun J, Dalton R M, Patel S, Howard W, Anderson E C, Barclay W S, Digard P J. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. Virology 2009, 83(16):8021-8031.
288. Wolstenholme A J, Barrett T, Nichol S T, Mahy B W. Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. J Virol 1980, 35: 1-7.
289. Wu Z, Earle J, Saito S, Anderson C W, Appella E, Xu Y. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol. Cell. Biol. 2002, 22: 2441-2449.
290. Wurzer W J, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 2003, 22: 2717-2718.
291. Wurzer W J, Ehrhardt C, Pleschka S, et al. NF-Kb dependent induction of TRAIL and Fas/FasL is crucial for efficient influenza virus propagation. J Biol. Chem. 2004, 279: 30931-30937.
292. Xiong Y, Hannon G J, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993, 366: 701-704.
293. Xirodimas D P, Saville M K, Bourdon J C, Hay R T, Lane D P. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 2004, 118: 83-97.
294. Yang Y, Ludwig R L, Jensen J P, Pierre S A, Medaglia M V, Davydov I V, Safiran Y J, Oberoi P, Kenten J H, Phillips A C, Weissman A M, Vousden K H. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005, 7: 547-559.
295. Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 2005, 331: 851-858.
296. Zamarin D, García-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 2005, 1: e4.
297. Zamarin D, Ortigoza M B, Palese P. Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 2006, 80: 7976-7983.
298. Zhan Q, Antinore M J, Wang X W, Carrier F, Smith M L, Harris C C, Fornace A J. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 1999, 18: 2892-2900.
299. Zhang J, Leser GP, Pekosz A, Lamb RA. The cytoplasmic tails of the influenza virus spike glycoproteins are required for normal genome packaging. Virology 2000, 269(2): 325-34.
300. Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998, 92(6):725-34
301. Zhang Y, Wolf G W, Bhat K, Jin A, Allio T, Burkhart W A, Xiong Y. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol. Cell. Biol. 2003, 23: 8902-8912.
302. Zhao W, Kruse J P, Tang Y, Jung S Y, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 2008, 451: 587–590.
303. Zhirnov O P. Isolation of matrix protein M1 from influenza viruses by acid-dependent extraction with nonionic detergent. Virology 1992, 186: 324-330
304. Zhirnov O P, Konakova T E, Wolff T, Klenk H D. 3NS1 protein of influenza A virus down-regulates apoptosis. J Virol 2002, 76: 1617-1625.
305. Zhu Q, Yang H, Chen W, Cao W, Zhong G, Jiao P, Deng G, Yu K, Yang C, Bu Z, Kawaoka Y, Chen H. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 2008, 82: 220-228.