一种新型p53负调控分子PACT的功能研究
|
摘要
抑癌蛋白p53是调控细胞周期进展及凋亡发生的蛋白网络的节点分子，作为一种重要的转录因子，在细胞应激，如DNA损伤、染色质异常、原癌基因激活或细胞非正常增殖时，p53迅速激活并聚集在细胞内，引起细胞周期阻滞或细胞凋亡。超过50％的人类肿瘤与p53的突变直接相关，它的结构改变和功能异常可能是这些肿瘤发生发展的重要环节。对p53活性的严格调节在维持细胞的正常生长和防止癌变等方面起着非常重要的作用。在生理状态下，p53的功能主要受蛋白质水平上的稳定性及活性的调节。p53的多种负调控分子，如HDM2、COP1、Sir2α、YY1等与之相互作用，使其活性维持在较低水平。本文鉴定了一个新的p53负调控分子PACT(P53 Associated Cellular protein-Testes derived)。PACT为p53、Rb结合蛋白，含锌指环结构域(Ring-finger domain)。其他分子的研究表明，该类结构域除作为蛋白质之间相互作用的结构基础外，还是泛素-蛋白水解酶体途径中泛素连接酶的标志性结构域。但PACT对p53的调控机制及其调控的生物学意义尚未揭示。本文的研究表明，PACT确实具有预期的泛素连接酶活性，它可以与HDM2相互作用，并通过影响HDM2-p53之间的结合，以HDM2依赖的方式促进p53泛素化，进而加速p53蛋白降解。同时，PACT基因的过表达还可以抑制p53的转录活性，并下调其靶基因p21的mRNA水平。除体外分子机制实验外，我们对PACT基因敲除的胚胎进行了分析，表明p21的mRNA水平明显上调，从整体及反面的角度验证了体外实验的结果。此外，通过在细胞内对PACT基因敲低表达，表明在p53野生型的细胞系中PACT的敲低会导致细胞凋亡比例明显上调，而在p53缺陷型细胞系中则不具有这种现象，说明PACT的敲低对细胞凋亡的影响依赖于p53的活性。随后进行的挽救实验表明，p53的缺失对于PACT基因敲除致死表型具有较为明显的挽救。以上结果证实了PACT是一种新的p53负调控分子，它的缺失会导致p53活性的部分失控，从而对细胞凋亡具有重要的调控意义。
The p53 tumor suppressor is a transcriptional factor that can induce either growth arrest or apoptosis and is frequently mutated or deleted in more than 50% of human cancers. However, the steady-state levels and transcriptional activity of p53 increase dramatically in cells that sustain various types of stress. In addition, many tumors retaining wide-type p53 often have defects in activating or responding to p53. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through post-translation modifications of p53. PACT (also known as P2P-R, RBBP6) is a RING finger-containing protein that can bind p53 in vitro and in vivo. Here, we demonstrated that PACT can inhibit the accumulation and promote the degradation of p53. Endogenous PACT can also interact with Hdm2 and promotes Hdm2-mediated ubiquitination of p53 due to enhancement of the assembly of the p53-Hdm2 complex. Depletion of endogenous PACT by RNAi results in p53 accumulation due to a reduction of p53 ubiquitination in vivo and induces apoptosis. Furthermore, disruption of PACT in mice leads to early embryonic lethality before 7.5 dpc accompanied by widespread apoptosis. More interestingly, introduction of a p53 null mutation into PACT~(-/-) embryos partially rescues the lethality phenotype and prolonges survival until E10.5. Taken together, these findings identify PACT as a potential cofactor for Hdm2 in the negative regulation of p53 and suggest a possible role for PACT in development and tumorigenesis.
The p53 tumor suppressor is a transcriptional factor that can induce either growth arrest or apoptosis and is frequently mutated or deleted in more than 50% of human cancers. However, the steady-state levels and transcriptional activity of p53 increase dramatically in cells that sustain various types of stress. In addition, many tumors retaining wide-type p53 often have defects in activating or responding to p53. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through post-translation modifications of p53. PACT (also known as P2P-R, RBBP6) is a RING finger-containing protein that can bind p53 in vitro and in vivo. Here, we demonstrated that PACT can inhibit the accumulation and promote the degradation of p53. Endogenous PACT can also interact with Hdm2 and promotes Hdm2-mediated ubiquitination of p53 due to enhancement of the assembly of the p53-Hdm2 complex. Depletion of endogenous PACT by RNAi results in p53 accumulation due to a reduction of p53 ubiquitination in vivo and induces apoptosis. Furthermore, disruption of PACT in mice leads to early embryonic lethality before 7.5 dpc accompanied by widespread apoptosis. More interestingly, introduction of a p53 null mutation into PACT~(-/-) embryos partially rescues the lethality phenotype and prolonges survival until E10.5. Taken together, these findings identify PACT as a potential cofactor for Hdm2 in the negative regulation of p53 and suggest a possible role for PACT in development and tumorigenesis.
引文
Adler, V., Pincus, M R., Minamoto, T., Fuchs, S., Bluth, M.J., BrandtRauf, P.W., Friedman, F.K., Robinson, R.C., Chen, J.M., Wang, X.W., et al. (1997). Conformation-dependent phosphorylation of p53. Proc. Natl. Acad. Sci. USA 94, 1686-1691.
Berger M, Vogt Sionov R, Levine AJ, Haupt Y. (2001). A role for the polyproline domain of p53 in its regulation by Mdm2. J Biol Chem. 276(6):3785-90.
Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004, 4(10):793-805.
Boyd, S.D., Tsai, K.Y., and Jacks, T. (2000). An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat. Cell Biol. 2, 563-568.
Brignone C, Bradley KE, Kisselev AF, Grossman SR. (2004). A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway. Oncogene. 23(23):4121-9.
Caceres JF, Misteli T, Screaton GR, Spector DL, Krainer AR. (1997). Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity. J Cell Biol. 138(2):225-38.
Cavaloc Y, Popielarz M, Fuchs JP, Gattoni R, Stevenin J. (1994). Characterization and cloning of the human splicing factor 9G8: a novel 35 kDa factor of the serine/arginine protein family. EMBO J. 13(11):2639-49.
Chernov MV, Bean LJ, Lerner N, Stark GR. (2001). Regulation of ubiquitination and degradation of p53 in unstressed cells through C-terminal phosphorylation. J Biol Chem. 276(34):31819-24.
Di Fruscio M, Chen T, Richard S. (1999). Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc Natl Acad Sci U S A. 96(6):2710-5.
Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y. (1999). Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol. 19(10):7237-44.
Dornan D, Wertz I, Shimizu H, Arnort D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM. (2004). The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature. 429(6987):86-92.
Ewen ME, Ludlow JW, Marsilio E, DeCaprio JA, Millikan RC, Cheng SH, Paucha E,Livingston DM. (1989). An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular protein, p120. Cell. 58(2):257-67.
Freedman, D.A., Wu, L., and Levine, A.J. (1999). Functions of the MDM2 oncoprotein. Cell. Mol. Life Sci. 55, 96-107.
Freemont PS. (2000). RING for destruction? Curr Biol, 10(2):R84-87.
Fuchs, S.Y., Adler, V., Buschmann, T., Yin, Z., Wu, X., Jones, S.N., and Ronai, Z. (1998). JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 12: 2658-2663.
Gao S, Witte MM, Scott RE. (2002). P2P-R protein localizes to the nucleolus of interphase cells and the periphery of chromosomes in mitotic cells which show maximum P2P-R immunoreactivity. J Cell Physiol. 191(2):145-54.
Gao S, Scott RE. (2002). P2P-R protein overexpression restricts mitotic progression at prometaphase and promotes mitotic apoptosis. J Cell Physiol. 193(2): 199-207.
Gao S, Scott RE. (2003). Stable overexpression of specific segments of the P2P-R protein in human MCF-7 cells promotes camptothecin-induced apoptosis. J Cell Physiol. 197(3):445-52.
Geyer, R.K., Yu, Z.K., and Maki, C.G (2000). The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol. 2(9):569-73.
Conaway, R.C., Conaway, J.W., and Branton, P.E. (2001). Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 15,3104-3117.
Gronroos E, Terentiev AA, Punga T, Ericsson J. (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci U S A. 101(33): 12165-70.
Hershko T, Chaussepied M, Oren M, Ginsberg D. (2005). Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ. 12(4):377-83.
Huang Y, Gattoni R, Stevenin J, Steitz JA. (2003). SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol Cell. 11(3):837-43.
Haupt, Y., Maya, R., Kazaz, A., and Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature 387,296-299.
Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J. (2005). The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 8(1):75-87.
Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. (2000). Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 6(1):96-9.
Joazeiro CA, Weissman AM. (2000). RING finger proteins: mediators of ubiquitin ligase activity. Cell. 102(5):549-52.
Jones SN, Roe AE, Donehower LA, Bradley A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 378(6553):206-8.
Jumaa H, Wei G, Nielsen PJ. (1999). Blastocyst formation is blocked in mouse embryos lacking the splicing factor SRp20. Curr Biol. 9(16):899-902.
Kramer A. (1996). The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem. 65:367-409.
Kubbutat, M.H., Jones, S.N., and Vousden, K.H. (1997). Regulation of p53 stability by Mdm2. Nature 387,299-303.
Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M. (2004). Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell. 5(5):465-75.
Labbaye C, Valtieri M, Grignani F, Puglisi R, Luchetti L, Masella B, Alcalay M, Testa U, Peschle C. (1999). Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis. Oncogene. 18(23):3529-40.
Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002 Jun 3;21(11):2672-81.
Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. 112(6):779-91.
Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997, 88:323-331.
Li HH, Li AG, Sheppard HM, Liu X. (2004). Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell. 13(6):867-78.
Li J, Hawkins IC, Harvey CD, Jennings JL, Link AJ, Patton JG (2003). Regulation of alternative splicing by SRrp86 and its interacting proteins. Mol Cell Biol. 23(21):7437-47.
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. (2003). Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science. 302(5652):1972-5.
Mak SK, Kultz D. (2004). Gadd45 proteins induce G2/M arrest and modulate apoptosis in kidney cells exposed to hyperosmotic stress. J Biol Chem. 279(37):39075-84.
McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M. (2003). The mammalian S1R2 J protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 23(l):38-54.
Michaelson JS, Bader D, Kuo F, Kozak C, Leder P. (1999). Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13(15):1918-23.
Montes de Oca Luna R, Wagner DS, Lozano G (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 378(6553):203-6.
Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. (1993). Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 362(6423):857-60.
Pearson M, Pelicci PG (2001). PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene. 20(49):7250-6.
Pickart, CM. (1997). Targeting of substrates to the 26S proteasome. FASEB J. 11,1055-1066.
Potuschak T, Stary S, Schlogelhofer P, Becker F, Nejinskaia V, Bachmair A. (1998). PRT1 of Arabidopsis thaliana encodes a component of the plant N-end rule pathway. Proc Natl Acad Sci U S A. 95(14):7904-8.
Pugh DJ, Ab E, Faro A, Lutya PT, Hoffmann E, Rees DJ. (2006). DWNN, a novel ubiquitin-like domain, implicates RBBP6 in mRNA processing and ubiquitin-like pathways. BMC Struct Biol. 6:1.
Rubin SM, Gall AL, Zheng N, Pavletich NP. (2005). Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell. 123(6):1093-106.
Sakai Y, Saijo M, Coelho K, Kishino T, Niikawa N, Taya Y. (1995). cDNA sequence and chromosomal localization of a novel human protein, RBQ-1 (RBBP6), that binds to the
retinoblastoma gene product. Genomics. 30(1):98-101.
Scheffner, M., Huibregtse, J.M., Vierstra, R.D., and Howley, P.M. (1993). The HPV-16 E6 and E6-AP complex functions as a ubiquitinprotein ligase in the ubiquitination of p53. Cell 75,495-505.
Schmidt D, Muller S. (2002). Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA. 99(5):2872-7.
Scott RE, Gao S. (2002). P2P-R deficiency modifies nocodazole-induced mitotic arrest and UV-induced apoptosis. Anticancer Res. 22(6C):3837-42.
Seeler JS, Dejean A. (2003). Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol. 4(9):690-9.
Shin C, Manley JL. (2002). The SR protein SRp38 represses splicing in M phase cells. Cell. 111(3):407-17.
Shin C, Feng Y, Manley JL. (2004). Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature. 427(6974):553-8.
Shirangi, T.R., Zaika, A., and Moll, U.M. (2002). Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage. FASEB J. 16,420-422.
Simons A, Melamed-Bessudo C, Wolkowicz R, Sperling J, Sperling R, Eisenbach L, Rotter V. (1997) PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb. Oncogene. 14(2): 145-55.
Steven R. Grossman, Maria E. Deato, Chrystelle Brignone, Ho Man Chan, Andrew L. Kung, Hideaki Tagami, Yoshihiro Nakatani, and David M. Livingston. (2003). Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300. Science. 300: 342-344.
Stommel, J.M., Marchenko, N.D., Jimenez, GS., Moll, U.M., Hope, T.J., and Wahl, GM. (1999). A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660-1672.
Sui G Affar el B, Shi Y, Brignone C, Wall NR, Yin P, Donohoe M, Luke MP, Calvo D, Grossman SR, Shi Y. (2004). Yin Yang 1 is a negative regulator of p53. Cell. 117(7):859-72.
Tretiakova M, Turkyilmaz M, Grushko T, Kocherginsky M, Rubin C, Teh B, Yang XJ. (2006). Topoisomerase II alpha in Wilms tumors: gene alterations and immunoexpression. J Clin Pathol. Mar 23;
van Der Houven Van Oordt W, Newton K, Screaton GR, Caceres JF. (2000). Role of SR protein modular domains in alternative splicing specificity in vivo. Nucleic Acids Res.
28(24):4822-31.
Vogelstein B, Lane D, Levine AJ. (2000). Surfing the p53 network. Nature. 408(6810):307-10.
Vousden KH, Lu X. (2002). Live or let die: the cell's response to p53. Nat. Rev. Cancer, 2(8):594-604.
Wang C, Ivanov A, Chen L, Fredericks WJ, Seto E, Rauscher FJ 3rd, Chen J. (2005). MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 24(18):3279-90.
Wen ST, Jackson PK, Van Etten RA. (1996). The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 15(7):1583-95.
Witte MM, Scott RE. (1997). The proliferation potential protein-related (P2P-R) gene with domains encoding heterogeneous nuclear ribonucleoprotein association and Rb1 binding shows repressed expression during terminal differentiation. Proc Natl Acad Sci U S A. 94(4): 1212-7.
Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR, Livingston DM. (1995). Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 375(6533):694-8.
Xirodimas, D., Saville, M.K., Edling, C, Lane, D.P., and Lain, S. (2001b). Different effects of pl4ARF on the levels of ubiquitinated p53 and Mdm2 in vivo. Oncogene 20,4972-4983.
Yang Y, Li CC, Weissman AM. (2004). Regulating the p53 system through ubiquitination. Oncogene. 23(11):2096-106.
Yoshitake Y, Nakatsura T, Monji M, Senju S, Matsuyoshi H, Tsukamoto H, Hosaka S, Komori H, Fukuma D, Ikuta Y, Katagiri T, Furukawa Y, Ito H, Shinohara M, Nakamura Y, Nishimura Y. (2004). Proliferation potential-related protein, an ideal esophageal cancer antigen for immunotherapy, identified using complementary DNA microarray analysis. Clin Cancer Res. 10(19):6437-48.
Zhang Y, Karas M, Zhao H, Yakar S, LeRoith D. (2004). 14-3-3sigma mediation of cell cycle progression is p53-independent in response to insulin-like growth factor-I receptor activation. J Biol Chem. 279(33):34353-60.
Zhu J, Zhang S, Jiang J, Chen X. (2000). Definition of the p53 functional domains necessary for inducing apoptosis. J Biol Chem. 275(51):39927-34.
Zhu JY, Abate M, Rice PW, Cole CN. (1991). The ability of simian virus 40 large T antigen to immortalize primary mouse embryo fibroblasts cosegregates with its ability to bind to p53. J Virol. 65(12): 6872-80.
李力博士论文，P43，图1—14
王建博士论文，P36-P381 DeLeo AB, Jay G, Appella E, et al. Proc. Natl. Acad. Sci. U S A, 1979, 76(5): 2420-4.
2 Nigro JM, Baker SJ, Preisinger AC, et al. Nature, 1989, 342(6250): 705-8.
3 Vogelstein B, Lane D, Levine AJ. Nature, 2000, 408(6810): 307-10.
4 Roger P. Leng, Yunping Lin, Weili Ma, et al. Cell, 2003, 112: 779-791.
5 Vousden KH, Lu X. Nat. Rev. Cancer, 2002, 2(8): 594-604.
6 Mihara, M. et al. Mol. Cell, 2003, 11: 577-590.
7 Elisa de Stanchina, Emmanuelle Querido, Masako Narita, et al. Mol. Cell, 2004, 13: 523-535.
8 Sari Kurki, Karita Peltonen, Leena Latonen, et al. Cancer Cell, 2004, 5: 465-475.
9 Hiroaki Higashitsuji, Hisako Higashitsuji, Katsuhiko Itoh, et al. Cancer Cell, 2005, 8: 75-87.
10 Guangchao Sui, El Bachir Affar, Yujiang Shi, et al. Cell, 2004, 117: 859-872.
11 Ann M. Bode, Zigang Dong, Nature, 2004, 4: 793-805.
12 Waterman, M. J, Stavridi, E. S, Waterman, J. L. et al. Nature Genet., 1998, 19: 175-178.
13 Fan G, Ma X, Wong P. Y, et al. Apoptosis, 2004, 9: 211-221.
14 Liu, L. et al. Mol. Cell. Biol., 1999, 19: 1202-1209.
15 Luo J, Su F, Chen D, et al. Nature, 2000, 408: 377-381.
16 Michael D, Oren M. Semin Cancer Biol., 2003, 13: 49-58.17 Li M, etal. Science, 2003, 302:1972-1975.
18 Goddard AD, Borrow J, Solomon E. Leukemia, 1992, Suppl 3:117S-119S.
19 Zhong S, Salomoni P, Pandolfi P P. Nature Cell Biol, 2000, 2:E85-E90.
20 Muratani M, et al. Nature Cell Biol, 2002, 4:106-110.
21 Pearson M, et al. Nature, 2000, 406:207-210.
22 Louria-Hayon I, et al. J. Biol. Chem., 2003, 278:33134-33141.
23 Rosa Bemardi, Pier Paolo Scaglioni, Stephan Bergmann, et al. Nature Cell Biol., 2004, 6:665-672.
24 Yanping Zhang, Yue Xiong, Wendell G Yarbrough. Cell, 1998,92: 725-734.
25 Highland JH, Howard GA. J. Biol. Chem, 1975, 250(3):813-814.
26 V Marechal, B Elenbaas, J Piette, et al. Mol. Cell Biol, 1994, 14:7414-7420.
27 Marion AE Lohrum, Robert L Ludwig, Michael HG Kubbutat, et al. Cancer Cell, 2003,3:577-587.
28 Masatoshi Takagi, Michael J Absalon, Kevin G McLure, et al. Cell, 2005, 123:49-63.
29 Takemura M, Ohoka F, Perpelescu M, et al. Exp. Cell Res,2002, 276(2):233-241.
30 Higashitsuji H, Itoh K, Nagao T, et al. Nat. Med, 2000, 6:96-99.
31 Simons A, Melamed-Bessudo C, Wolkowicz R, et al. Oncogene. 1997, 14(2): 145-55.
32 Witte MM, Scott RE. Proc. Natl. Acad. Sci. USA. 1997, 94(4):1212-7.
[1] Strous GJ, Govers R. The ubiquitin-proteasome system and endocytosis[J]. J Cell Sci, 1999, 112: 1417-23.
[2] Rebecca L. Welchman, Colin Gordon, R. John Mayer. Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nature, 2005, 6: 599-609.
[3] Haas AL, Siepmann TJ. Pathways of ubiquitin conjugation, FASEB J. 1997 Dec; 11(14): 1257-65.
[4] Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem, 2001, 70: 503-33.
[5] Shirakura H, Hayashi N, Ogino S, et al. Caspase recruitment domain of procaspase-2 could be a target for SUMO-1 modification through Ubc9. Biochem Biophys Res Commun, 2005, 331: 1007-15.[6] Sun L, Trausch-Azar JS, Ciechanover A, et al. Ubiquitin-proteasome-mediated degradation, intracellular localization, and protein synthesis of MyoD and Id1 during muscle differentiation. J Biol Chem, 2005, 280:26448-56.
[7] Aviel S, Winberg G, Massucci M, et al. Degradation of the epstein-barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem, 2000,275:23491-9.
[8] Reinstein E, Scheffner M, Oren M, et al. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene, 2000, 19:5944-50.
[9] Beaudenon S, Dastur A, Huibregtse JM. Expression and assay of HECT domain ligases. Methods Enzymol, 2005, 398:112-25.
[10] Freemont PS. RING for destruction? Curr Biol, 2000, 10:R84-7.
[11] Rubin C, Gur G, Yarden Y. Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation. Cell Res, 2005,15:66-71.
[12] Deshaies RJ. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol. 1999; 15:435-67.
[13] Castro A, Bernis C, Vigneron S, et al. The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene, 2005, 24:314-25.
[14] Hatakeyama S, Nakayama KI. U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun, 2003, 302:635-45.
[15] Baboshina OV, Crinelli R, Siepmann TJ, et al. N-end rule specificity within the ubiquitin/proteasome pathway is not an affinity effect. J Biol Chem, 2001,276:39428-37.
[16] Turner GC, Du F, Varshavsky A. Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway. Nature, 2000,405:579-83.
[17] Velasco-Sampayo A, Alemany S. p27~(kip) protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. J Immunol, 2001, 166:6084-90.
[18] Hay RT. SUMO: a history of modification. Mol Cell, 2005, 18:1-12.
[19] Hoege C, Pfander B, Moldovan GL, et al. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature, 2002,419:135-41.
[20] Philipp Stelter, Helle D. Ulrich. Control of spontaneous and damage-induced mutagenesis by??SUMO and ubiquitin conjugation. Nature, 425:188-191.
[21] Lajos Haracska, Carlos A. Torres-Ramos, Robert E. Johnson, et al. Opposing Effects of Ubiquitin Conjugation and SUMO Modification of PCNA on Replicational Bypass of DNA Lesions in Saccharomyces cerevisiae. Mol. Cell. Biol, 2004, 24:4267-4274.
[22] Zu-Wen Sun, C. David Allis. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature, 418:104-108.
[23] Xirodimas DP, Saville MK, Bourdon JC, et al. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell, 2004,118:83-97.
[24] Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol, 2000, 18:621-63.
[25] Lemmon SK, Traub LM. Sorting in the endosomal system in yeast and animal cells. Curr Opin Cell Biol, 2000,12:457-66.
Berger M, Vogt Sionov R, Levine AJ, Haupt Y. (2001). A role for the polyproline domain of p53 in its regulation by Mdm2. J Biol Chem. 276(6):3785-90.
Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004, 4(10):793-805.
Boyd, S.D., Tsai, K.Y., and Jacks, T. (2000). An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat. Cell Biol. 2, 563-568.
Brignone C, Bradley KE, Kisselev AF, Grossman SR. (2004). A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway. Oncogene. 23(23):4121-9.
Caceres JF, Misteli T, Screaton GR, Spector DL, Krainer AR. (1997). Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity. J Cell Biol. 138(2):225-38.
Cavaloc Y, Popielarz M, Fuchs JP, Gattoni R, Stevenin J. (1994). Characterization and cloning of the human splicing factor 9G8: a novel 35 kDa factor of the serine/arginine protein family. EMBO J. 13(11):2639-49.
Chernov MV, Bean LJ, Lerner N, Stark GR. (2001). Regulation of ubiquitination and degradation of p53 in unstressed cells through C-terminal phosphorylation. J Biol Chem. 276(34):31819-24.
Di Fruscio M, Chen T, Richard S. (1999). Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc Natl Acad Sci U S A. 96(6):2710-5.
Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y. (1999). Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol. 19(10):7237-44.
Dornan D, Wertz I, Shimizu H, Arnort D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM. (2004). The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature. 429(6987):86-92.
Ewen ME, Ludlow JW, Marsilio E, DeCaprio JA, Millikan RC, Cheng SH, Paucha E,Livingston DM. (1989). An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular protein, p120. Cell. 58(2):257-67.
Freedman, D.A., Wu, L., and Levine, A.J. (1999). Functions of the MDM2 oncoprotein. Cell. Mol. Life Sci. 55, 96-107.
Freemont PS. (2000). RING for destruction? Curr Biol, 10(2):R84-87.
Fuchs, S.Y., Adler, V., Buschmann, T., Yin, Z., Wu, X., Jones, S.N., and Ronai, Z. (1998). JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 12: 2658-2663.
Gao S, Witte MM, Scott RE. (2002). P2P-R protein localizes to the nucleolus of interphase cells and the periphery of chromosomes in mitotic cells which show maximum P2P-R immunoreactivity. J Cell Physiol. 191(2):145-54.
Gao S, Scott RE. (2002). P2P-R protein overexpression restricts mitotic progression at prometaphase and promotes mitotic apoptosis. J Cell Physiol. 193(2): 199-207.
Gao S, Scott RE. (2003). Stable overexpression of specific segments of the P2P-R protein in human MCF-7 cells promotes camptothecin-induced apoptosis. J Cell Physiol. 197(3):445-52.
Geyer, R.K., Yu, Z.K., and Maki, C.G (2000). The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol. 2(9):569-73.
Conaway, R.C., Conaway, J.W., and Branton, P.E. (2001). Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 15,3104-3117.
Gronroos E, Terentiev AA, Punga T, Ericsson J. (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci U S A. 101(33): 12165-70.
Hershko T, Chaussepied M, Oren M, Ginsberg D. (2005). Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ. 12(4):377-83.
Huang Y, Gattoni R, Stevenin J, Steitz JA. (2003). SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol Cell. 11(3):837-43.
Haupt, Y., Maya, R., Kazaz, A., and Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature 387,296-299.
Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J. (2005). The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 8(1):75-87.
Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. (2000). Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 6(1):96-9.
Joazeiro CA, Weissman AM. (2000). RING finger proteins: mediators of ubiquitin ligase activity. Cell. 102(5):549-52.
Jones SN, Roe AE, Donehower LA, Bradley A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 378(6553):206-8.
Jumaa H, Wei G, Nielsen PJ. (1999). Blastocyst formation is blocked in mouse embryos lacking the splicing factor SRp20. Curr Biol. 9(16):899-902.
Kramer A. (1996). The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem. 65:367-409.
Kubbutat, M.H., Jones, S.N., and Vousden, K.H. (1997). Regulation of p53 stability by Mdm2. Nature 387,299-303.
Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M. (2004). Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell. 5(5):465-75.
Labbaye C, Valtieri M, Grignani F, Puglisi R, Luchetti L, Masella B, Alcalay M, Testa U, Peschle C. (1999). Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis. Oncogene. 18(23):3529-40.
Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002 Jun 3;21(11):2672-81.
Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. 112(6):779-91.
Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997, 88:323-331.
Li HH, Li AG, Sheppard HM, Liu X. (2004). Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell. 13(6):867-78.
Li J, Hawkins IC, Harvey CD, Jennings JL, Link AJ, Patton JG (2003). Regulation of alternative splicing by SRrp86 and its interacting proteins. Mol Cell Biol. 23(21):7437-47.
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. (2003). Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science. 302(5652):1972-5.
Mak SK, Kultz D. (2004). Gadd45 proteins induce G2/M arrest and modulate apoptosis in kidney cells exposed to hyperosmotic stress. J Biol Chem. 279(37):39075-84.
McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M. (2003). The mammalian S1R2 J protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 23(l):38-54.
Michaelson JS, Bader D, Kuo F, Kozak C, Leder P. (1999). Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13(15):1918-23.
Montes de Oca Luna R, Wagner DS, Lozano G (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 378(6553):203-6.
Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. (1993). Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 362(6423):857-60.
Pearson M, Pelicci PG (2001). PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene. 20(49):7250-6.
Pickart, CM. (1997). Targeting of substrates to the 26S proteasome. FASEB J. 11,1055-1066.
Potuschak T, Stary S, Schlogelhofer P, Becker F, Nejinskaia V, Bachmair A. (1998). PRT1 of Arabidopsis thaliana encodes a component of the plant N-end rule pathway. Proc Natl Acad Sci U S A. 95(14):7904-8.
Pugh DJ, Ab E, Faro A, Lutya PT, Hoffmann E, Rees DJ. (2006). DWNN, a novel ubiquitin-like domain, implicates RBBP6 in mRNA processing and ubiquitin-like pathways. BMC Struct Biol. 6:1.
Rubin SM, Gall AL, Zheng N, Pavletich NP. (2005). Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell. 123(6):1093-106.
Sakai Y, Saijo M, Coelho K, Kishino T, Niikawa N, Taya Y. (1995). cDNA sequence and chromosomal localization of a novel human protein, RBQ-1 (RBBP6), that binds to the
retinoblastoma gene product. Genomics. 30(1):98-101.
Scheffner, M., Huibregtse, J.M., Vierstra, R.D., and Howley, P.M. (1993). The HPV-16 E6 and E6-AP complex functions as a ubiquitinprotein ligase in the ubiquitination of p53. Cell 75,495-505.
Schmidt D, Muller S. (2002). Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA. 99(5):2872-7.
Scott RE, Gao S. (2002). P2P-R deficiency modifies nocodazole-induced mitotic arrest and UV-induced apoptosis. Anticancer Res. 22(6C):3837-42.
Seeler JS, Dejean A. (2003). Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol. 4(9):690-9.
Shin C, Manley JL. (2002). The SR protein SRp38 represses splicing in M phase cells. Cell. 111(3):407-17.
Shin C, Feng Y, Manley JL. (2004). Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature. 427(6974):553-8.
Shirangi, T.R., Zaika, A., and Moll, U.M. (2002). Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage. FASEB J. 16,420-422.
Simons A, Melamed-Bessudo C, Wolkowicz R, Sperling J, Sperling R, Eisenbach L, Rotter V. (1997) PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb. Oncogene. 14(2): 145-55.
Steven R. Grossman, Maria E. Deato, Chrystelle Brignone, Ho Man Chan, Andrew L. Kung, Hideaki Tagami, Yoshihiro Nakatani, and David M. Livingston. (2003). Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300. Science. 300: 342-344.
Stommel, J.M., Marchenko, N.D., Jimenez, GS., Moll, U.M., Hope, T.J., and Wahl, GM. (1999). A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660-1672.
Sui G Affar el B, Shi Y, Brignone C, Wall NR, Yin P, Donohoe M, Luke MP, Calvo D, Grossman SR, Shi Y. (2004). Yin Yang 1 is a negative regulator of p53. Cell. 117(7):859-72.
Tretiakova M, Turkyilmaz M, Grushko T, Kocherginsky M, Rubin C, Teh B, Yang XJ. (2006). Topoisomerase II alpha in Wilms tumors: gene alterations and immunoexpression. J Clin Pathol. Mar 23;
van Der Houven Van Oordt W, Newton K, Screaton GR, Caceres JF. (2000). Role of SR protein modular domains in alternative splicing specificity in vivo. Nucleic Acids Res.
28(24):4822-31.
Vogelstein B, Lane D, Levine AJ. (2000). Surfing the p53 network. Nature. 408(6810):307-10.
Vousden KH, Lu X. (2002). Live or let die: the cell's response to p53. Nat. Rev. Cancer, 2(8):594-604.
Wang C, Ivanov A, Chen L, Fredericks WJ, Seto E, Rauscher FJ 3rd, Chen J. (2005). MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 24(18):3279-90.
Wen ST, Jackson PK, Van Etten RA. (1996). The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 15(7):1583-95.
Witte MM, Scott RE. (1997). The proliferation potential protein-related (P2P-R) gene with domains encoding heterogeneous nuclear ribonucleoprotein association and Rb1 binding shows repressed expression during terminal differentiation. Proc Natl Acad Sci U S A. 94(4): 1212-7.
Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR, Livingston DM. (1995). Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 375(6533):694-8.
Xirodimas, D., Saville, M.K., Edling, C, Lane, D.P., and Lain, S. (2001b). Different effects of pl4ARF on the levels of ubiquitinated p53 and Mdm2 in vivo. Oncogene 20,4972-4983.
Yang Y, Li CC, Weissman AM. (2004). Regulating the p53 system through ubiquitination. Oncogene. 23(11):2096-106.
Yoshitake Y, Nakatsura T, Monji M, Senju S, Matsuyoshi H, Tsukamoto H, Hosaka S, Komori H, Fukuma D, Ikuta Y, Katagiri T, Furukawa Y, Ito H, Shinohara M, Nakamura Y, Nishimura Y. (2004). Proliferation potential-related protein, an ideal esophageal cancer antigen for immunotherapy, identified using complementary DNA microarray analysis. Clin Cancer Res. 10(19):6437-48.
Zhang Y, Karas M, Zhao H, Yakar S, LeRoith D. (2004). 14-3-3sigma mediation of cell cycle progression is p53-independent in response to insulin-like growth factor-I receptor activation. J Biol Chem. 279(33):34353-60.
Zhu J, Zhang S, Jiang J, Chen X. (2000). Definition of the p53 functional domains necessary for inducing apoptosis. J Biol Chem. 275(51):39927-34.
Zhu JY, Abate M, Rice PW, Cole CN. (1991). The ability of simian virus 40 large T antigen to immortalize primary mouse embryo fibroblasts cosegregates with its ability to bind to p53. J Virol. 65(12): 6872-80.
李力博士论文，P43，图1—14
王建博士论文，P36-P381 DeLeo AB, Jay G, Appella E, et al. Proc. Natl. Acad. Sci. U S A, 1979, 76(5): 2420-4.
2 Nigro JM, Baker SJ, Preisinger AC, et al. Nature, 1989, 342(6250): 705-8.
3 Vogelstein B, Lane D, Levine AJ. Nature, 2000, 408(6810): 307-10.
4 Roger P. Leng, Yunping Lin, Weili Ma, et al. Cell, 2003, 112: 779-791.
5 Vousden KH, Lu X. Nat. Rev. Cancer, 2002, 2(8): 594-604.
6 Mihara, M. et al. Mol. Cell, 2003, 11: 577-590.
7 Elisa de Stanchina, Emmanuelle Querido, Masako Narita, et al. Mol. Cell, 2004, 13: 523-535.
8 Sari Kurki, Karita Peltonen, Leena Latonen, et al. Cancer Cell, 2004, 5: 465-475.
9 Hiroaki Higashitsuji, Hisako Higashitsuji, Katsuhiko Itoh, et al. Cancer Cell, 2005, 8: 75-87.
10 Guangchao Sui, El Bachir Affar, Yujiang Shi, et al. Cell, 2004, 117: 859-872.
11 Ann M. Bode, Zigang Dong, Nature, 2004, 4: 793-805.
12 Waterman, M. J, Stavridi, E. S, Waterman, J. L. et al. Nature Genet., 1998, 19: 175-178.
13 Fan G, Ma X, Wong P. Y, et al. Apoptosis, 2004, 9: 211-221.
14 Liu, L. et al. Mol. Cell. Biol., 1999, 19: 1202-1209.
15 Luo J, Su F, Chen D, et al. Nature, 2000, 408: 377-381.
16 Michael D, Oren M. Semin Cancer Biol., 2003, 13: 49-58.17 Li M, etal. Science, 2003, 302:1972-1975.
18 Goddard AD, Borrow J, Solomon E. Leukemia, 1992, Suppl 3:117S-119S.
19 Zhong S, Salomoni P, Pandolfi P P. Nature Cell Biol, 2000, 2:E85-E90.
20 Muratani M, et al. Nature Cell Biol, 2002, 4:106-110.
21 Pearson M, et al. Nature, 2000, 406:207-210.
22 Louria-Hayon I, et al. J. Biol. Chem., 2003, 278:33134-33141.
23 Rosa Bemardi, Pier Paolo Scaglioni, Stephan Bergmann, et al. Nature Cell Biol., 2004, 6:665-672.
24 Yanping Zhang, Yue Xiong, Wendell G Yarbrough. Cell, 1998,92: 725-734.
25 Highland JH, Howard GA. J. Biol. Chem, 1975, 250(3):813-814.
26 V Marechal, B Elenbaas, J Piette, et al. Mol. Cell Biol, 1994, 14:7414-7420.
27 Marion AE Lohrum, Robert L Ludwig, Michael HG Kubbutat, et al. Cancer Cell, 2003,3:577-587.
28 Masatoshi Takagi, Michael J Absalon, Kevin G McLure, et al. Cell, 2005, 123:49-63.
29 Takemura M, Ohoka F, Perpelescu M, et al. Exp. Cell Res,2002, 276(2):233-241.
30 Higashitsuji H, Itoh K, Nagao T, et al. Nat. Med, 2000, 6:96-99.
31 Simons A, Melamed-Bessudo C, Wolkowicz R, et al. Oncogene. 1997, 14(2): 145-55.
32 Witte MM, Scott RE. Proc. Natl. Acad. Sci. USA. 1997, 94(4):1212-7.
[1] Strous GJ, Govers R. The ubiquitin-proteasome system and endocytosis[J]. J Cell Sci, 1999, 112: 1417-23.
[2] Rebecca L. Welchman, Colin Gordon, R. John Mayer. Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nature, 2005, 6: 599-609.
[3] Haas AL, Siepmann TJ. Pathways of ubiquitin conjugation, FASEB J. 1997 Dec; 11(14): 1257-65.
[4] Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem, 2001, 70: 503-33.
[5] Shirakura H, Hayashi N, Ogino S, et al. Caspase recruitment domain of procaspase-2 could be a target for SUMO-1 modification through Ubc9. Biochem Biophys Res Commun, 2005, 331: 1007-15.[6] Sun L, Trausch-Azar JS, Ciechanover A, et al. Ubiquitin-proteasome-mediated degradation, intracellular localization, and protein synthesis of MyoD and Id1 during muscle differentiation. J Biol Chem, 2005, 280:26448-56.
[7] Aviel S, Winberg G, Massucci M, et al. Degradation of the epstein-barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem, 2000,275:23491-9.
[8] Reinstein E, Scheffner M, Oren M, et al. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue. Oncogene, 2000, 19:5944-50.
[9] Beaudenon S, Dastur A, Huibregtse JM. Expression and assay of HECT domain ligases. Methods Enzymol, 2005, 398:112-25.
[10] Freemont PS. RING for destruction? Curr Biol, 2000, 10:R84-7.
[11] Rubin C, Gur G, Yarden Y. Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation. Cell Res, 2005,15:66-71.
[12] Deshaies RJ. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol. 1999; 15:435-67.
[13] Castro A, Bernis C, Vigneron S, et al. The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene, 2005, 24:314-25.
[14] Hatakeyama S, Nakayama KI. U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun, 2003, 302:635-45.
[15] Baboshina OV, Crinelli R, Siepmann TJ, et al. N-end rule specificity within the ubiquitin/proteasome pathway is not an affinity effect. J Biol Chem, 2001,276:39428-37.
[16] Turner GC, Du F, Varshavsky A. Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway. Nature, 2000,405:579-83.
[17] Velasco-Sampayo A, Alemany S. p27~(kip) protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. J Immunol, 2001, 166:6084-90.
[18] Hay RT. SUMO: a history of modification. Mol Cell, 2005, 18:1-12.
[19] Hoege C, Pfander B, Moldovan GL, et al. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature, 2002,419:135-41.
[20] Philipp Stelter, Helle D. Ulrich. Control of spontaneous and damage-induced mutagenesis by??SUMO and ubiquitin conjugation. Nature, 425:188-191.
[21] Lajos Haracska, Carlos A. Torres-Ramos, Robert E. Johnson, et al. Opposing Effects of Ubiquitin Conjugation and SUMO Modification of PCNA on Replicational Bypass of DNA Lesions in Saccharomyces cerevisiae. Mol. Cell. Biol, 2004, 24:4267-4274.
[22] Zu-Wen Sun, C. David Allis. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature, 418:104-108.
[23] Xirodimas DP, Saville MK, Bourdon JC, et al. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell, 2004,118:83-97.
[24] Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol, 2000, 18:621-63.
[25] Lemmon SK, Traub LM. Sorting in the endosomal system in yeast and animal cells. Curr Opin Cell Biol, 2000,12:457-66.