p53在I型干扰素介导的先天性抗甲型流感病毒中的作用研究
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摘要
肿瘤抑制因子p53被称为“基因组卫士”，在细胞的DNA修复过程中发挥着极为重要的作用。同时p53在细胞中具有诱导细胞凋亡、参与细胞周期捕获、参与细胞代谢和抗病毒等功能。流感病毒感染细胞后，p53的表达量得以累积，IRF9的表达也明显上升。流感病毒感染p53敲除型小鼠与p53野生型小鼠后，p53敲除型小鼠的临床症状、肺脏的病理变化及流感病毒滴度均要严重于p53野生型小鼠。这表明p53与宿主抗流感病毒反应具有着密切的关系。
本研究首先利用流感病毒感染p53正常及p53下调表达的A549细胞，对细胞中病毒的复制水平和病毒滴度差异进行比较，了解清楚p53是否直接参与细胞抑制流感病毒复制的过程。同时检测Ⅰ型干扰素信号通路中多个抗病毒基因的表达差异，间接反映流感病毒感染后，p53对Ⅰ型干扰素信号通路的影响。结果表明，流感病毒感染后，p53直接影响着Ⅰ型干扰素信号通路中多个抗病毒相关基因的表达；下调p53表达后，IRF9、IRF7、RIG-I、ISG20、ISG15、GBP1和OAS1等多个基因的mRNA表达量均显著下降。Ⅰ型干扰素通路在机体抗流感过程中发挥着非常重要的作用。这表明流感病毒感染后，p53可以通过影响Ⅰ型干扰素通路而参与宿主抗流感病毒作用。为了进一步验证这种关系并不是单纯由于流感病毒所引起，而是p53与Ⅰ型干扰素通路之间直接的联系。我们利用Ⅰ型干扰素处理p53正常及p53下调表达的细胞，检测了Ⅰ型干扰素信号通路中多个抗病毒基因的表达差异。结果发现了与流感病毒感染后相类似的结果，而且差异程度较流感病毒感染后所表现的更为明显。同时，通过Ⅰ型干扰素对干扰素刺激应答元件(ISRE)的激活实验，我们发现ISRE的激活必须要有p53的存在才能够完全激活，这些结果均表明p53具有直接促进Ⅰ型干扰素通路激活的功能。p53启动子序列中被报道含有Ⅰ型干扰素作用元件，Ⅰ型干扰素可以转录调控p53的表达。而本研究发现p53具有直接促进Ⅰ型干扰素通路激活的功能。这表明p53与Ⅰ型干扰素可以相互促进、相互协调发挥抗病毒作用。
Ⅰ型干扰素在机体发挥抗流感过程中发挥着极其重要的作用。GBP1作为干扰素诱导的抗病毒蛋白已被报道可以抑制多种病毒的复制，但关于GBP1是否在流感病毒感染过程中发挥着抗病毒作用至今仍没有报道。最近，有报道发现流感病毒感染后GBP1的表达量显著上调。干扰素诱导的GBP1的表达可以被流感病毒抑制。这些研究结果表明GBP1与流感之间存在着一定的联系。本研究通过hGBP1的过表达实验证明了hGBP1具有抑制流感病毒复制的能力。hGBP1K51A的突变会使得hGBP1丧失其与GTP结合的能力，进而导致GTPase活性的丧失。hGBP1K51A的过表达不能够抑制流感病毒的复制，这表明GTPase活性是hGBP1发挥抑制流感病毒复制所必需的。NS1作为流感病毒拮抗宿主免疫反应的重要分子，可以与多类抗病毒蛋白直接结合，拮抗这些蛋白的抗病毒能力。我们研究发现NS1也可以和hGBP1相结合，NS1效应区123～144位氨基酸组成的片段与hGBP1第51位赖氨酸是两者相结合所必需的关键位点。GTPase是hGBP1发挥抗流感病毒的重要基础。那么NS1是否会抑制hGBP1的GTPase活性？研究发现NS1可以显著抑制hGBP1的GTPase活性，进而拮抗hGBP1介导的抗流感病毒能力。总之，流感病毒感染后，细胞的hGBP1在转录和蛋白水平上均显著上升。过表达hGBP1可以抑制流感病毒的复制。hGBP1第51位赖氨酸是hGBP1发挥抗流感作用所必需的。流感病毒NS1可以与hGBP1相结合，hGBP1第51位赖氨酸和NS1第123-144位氨基酸片段是两者发生结合所不可缺少的。NS1可以抑制hGBP1的GTPase活性，进而拮抗hGBP1发挥的抗病毒作用。hGBP1在机体发挥抗流感病毒免疫过程中具有着重要作用，流感病毒NS1可以显著拮抗这种抗病毒能力。
hGBP1被证明具有抑制流感病毒复制的能力。干扰素、IL-β及LPS等均可以诱导hGBP1的表达。p53作为一种转录因子，与干扰素通路具有着密切关系，p53已被报道可以转录调控多个干扰素诱导基因的表达。本实验室前期研究发现，流感病毒感染p53基因敲除小鼠后，GBP1的表达量明显低于p53野生型小鼠中GBP1的表达量。这表明GBP1与p53之间或许存在着一定的联系。通过ChIP on Chip进行高通量分析后，我们发现GBP1启动子序列能够和p53相结合。而进一步研究发现hGBP1的确为p53的靶基因。DNA损伤、病毒感染及细胞因子的刺激均可以通过影响p53而影响到hGBP1的表达。hGBP1启动子序列-4141～-4112和-2440～-2416两个基序为p53的结合反应元件。p53可以通过转录调控hGBP1的表达发挥抗病毒及抗肿瘤效应。该研究为进一步研究p53抗肿瘤和抗病毒的分子机制，以及开发抗病毒、抗肿瘤药物可以提供一定的参考依据。
总之，本研究证明了p53与Ⅰ型干扰素通路之间存在着紧密的联系，p53具有直接促进Ⅰ型干扰素通路激活的功能。p53与Ⅰ型干扰素可以相互促进、相互协调发挥抗流感病毒的作用。hGBP1被证明具有抑制流感病毒复制的能力，其为p53下游的靶基因。p53可以通过转录调控hGBP1的表达发挥抗病毒及抗肿瘤效应。这些研究结果，为今后进一步研究宿主的先天性抗流感病毒的反应机制，提高机体抗流感病毒能力提供了药物设计的靶标分子。为控制流感病毒在畜牧业中的危害提供理论基础，也为人类防治流感病毒的蔓延和扩散提供了一定的视角。
Tumor suppressor p53is widely known as ‘the guardian of the genome’, that performs importantfunctions in DNA repair process. In addition, p53has also been proven to regulate various biologicalprocesses such as cellular apoptosis, cell cycle arrest, cellular metabolism and antiviral responses.Influenza A virus (IAV) infection can induce the accumulation of p53, which results also in theupregulation of IRF9. The clinical symptoms, pathological responses and the viral loads of p53knockout (p53KO) mice shows much more severe than p53wildtype (p53WT) mice after IAV infection.All these results imply an important role of p53to perform antiviral activity against IAV infection.
A549cells with regular and deficient expression levels of p53were infected by IAV respectively. Theviral replication ability and the viral titers of the cells were determined and compared to understand theeffects of p53in IAV infection. Besides, the expression of several antiviral related genes in type Iinterferon (type I IFN) signaling pathway were detected to confirm that p53can affect the activation oftype I IFN signaling pathway during IAV infection. The results indicated that, p53directly affects theexpression of several antiviral related genes in type I IFN signaling pathway. Impaired expression ofantiviral related genes was found in the p53knockdown (p53KD) A549cells during IAV infection, suchas IRF9, IRF7, RIG-I, ISG20, ISG15, GBP1and OAS1. The IFN signaling pathway plays a key role inregulation of immune response against IAV infection，the results suggested that p53performs anti-IAVability through regulating the activation of type I IFN signaling pathway. To further prove the regulationof p53to type I IFN signaling pathway is an universal response, but not just in IAV infection cells. A549cells with regular and deficient expression levels of p53were treated with type I IFN, the expression ofseveral antiviral related genes in type I IFN signaling pathway were detected. In response to type I IFN,the impaired expression of antiviral related genes was also found in the p53KD cells, the impairedextent was more notable than the IAV infection groups. In addition, p53was found to be essential forthe activation of IFN-stimulated response elements (ISREs) induced by type I IFN. These resultsindicated p53can reinforce type I IFN signaling pathway. The promoter sequence of p53contains ISREfor type I IFN, so type I IFN can upregulate p53expression. Our results demonstrated p53can reinforcetype I IFN signaling pathway. It suggests a crosstalk between the p53and type I IFN pathway, p53andtype I IFN cooperates with each other to defend the cells from virus infection.
Type I IFN is indispensable for host to perform antiviral effects against IAV. GBP1has beenreported to possess the antiviral activity against several viruses. But whether IAV is inhibited by GBP1is still not clear. It is reported that, IAV infection induces GBP1expression, IAV inhibits the productionof GBP1induced by IFN. It suggests that GBP1may be involved in antiviral responses during IAVinfection. Overexpression of hGBP1was found to inhibit IAV replication in this study. The K51locatedin the highly conserved phosphate-binding loop of hGBP1is critical for its biological activity andfunction. Mutation of lysine51to alanine (K51A) abrogates GTP binding, dimerization, and GTPhydrolysis. Overexpression of hGBP1K51A failed to inhibit IAV replication, which suggests the GTPase of hGBP1is essential for its anti-IAV activity. NS1is widely known as an antagonist of hostimmune response to facilitate IAV replication. NS1was reported to interact with various anti-IAVproteins to antagonize their antiviral activity. NS1was also found to interact directly with hGBP1. Theresidues of123-144in the effector domain of NS1were required for the binding. The K51of hGBP1also decided the interaction. GTPase was proved to be essential for hGBP1to inhibit IAV replication;we predicted that NS1binds with hGBP1perhaps affects its GTPase activity. The ELIPA assay wascarried out to confirm this deduction, which showed the GTPase activity of hGBP1was significantlyimpaired by NS1. NS1clearly antagonized the anti-IAV activity of hGBP1. In conclusion, IAV infectiontriggers hGBP1expression. hGBP1possesses the anti-IAV activity, the GTPase of hGBP1is essentialfor its anti-IAV activity; the GTPase is dependent on the51K residue. NS1of IAV interacts with hGBP1,the51K of hGBP1and the residues of123-144of NS1are required for the interaction. NS1inhibits theGTPase of hGBP1to antagonize the anti-IAV activity of hGBP1. hGBP1shows an important effect inthe anti-IAV responses, NS1can weaken hGBP1-mediated anti-IAV ability.
Now, hGBP1is proved to possess anti-IAV activity. hGBP1expression can be induced by IFN, IL-βand LPS. p53, as a transcription factor shows important effect on IFN signaling pathway. Many ISGshave been proved to be p53transcriptional target genes. Our previous study showed that IAV infectioninduced GBP1expression was significantly impaired in p53KO mice compared with p53WT mice;which implied p53may correlate with GBP1expression. ChIP on Chip assay was carried out to identifythe potential transcriptional target genes of p53. The promoter sequence of GBP1was found to bindwith p53, and GBP1was identified as a potential target gene. We further confirmed that hGBP1is adirect transcriptional target gene of p53. DNA damage, viral infection and cytokines triggeredexpression of hGBP1was clearly regulated by p53. The fragments of-4141/-4112and-2440/-2416athGBP1promoter sequence were confirmed as the p53response elements. All these results indicated p53may transactivate hGBP1gene to perform the antiviral and antitumor activity. In conclusion, theseresults provided a new insight into antiviral and antitumor therapy and paved the way for future researchin p53functions.
In briefly, this study proved the correlation between p53and type I IFN pathway. p53possesses theability of enforcing type I IFN pathway activation. p53cooperates with type I IFN to perform anti-IAVresponses. hGBP1gene is a target gene of p53, p53upregulates hGBP1expression to carry out theantiviral and antitumor effects. Overall, all the results in this study provided a theoretical basis for hostanti-IAV immune responses research and anti-IAV strategies application to prevent the threat, damageand economic loss caused by IAV infection; which also offered several target molecules for anti-IAVmedicines development.
本研究首先利用流感病毒感染p53正常及p53下调表达的A549细胞，对细胞中病毒的复制水平和病毒滴度差异进行比较，了解清楚p53是否直接参与细胞抑制流感病毒复制的过程。同时检测Ⅰ型干扰素信号通路中多个抗病毒基因的表达差异，间接反映流感病毒感染后，p53对Ⅰ型干扰素信号通路的影响。结果表明，流感病毒感染后，p53直接影响着Ⅰ型干扰素信号通路中多个抗病毒相关基因的表达；下调p53表达后，IRF9、IRF7、RIG-I、ISG20、ISG15、GBP1和OAS1等多个基因的mRNA表达量均显著下降。Ⅰ型干扰素通路在机体抗流感过程中发挥着非常重要的作用。这表明流感病毒感染后，p53可以通过影响Ⅰ型干扰素通路而参与宿主抗流感病毒作用。为了进一步验证这种关系并不是单纯由于流感病毒所引起，而是p53与Ⅰ型干扰素通路之间直接的联系。我们利用Ⅰ型干扰素处理p53正常及p53下调表达的细胞，检测了Ⅰ型干扰素信号通路中多个抗病毒基因的表达差异。结果发现了与流感病毒感染后相类似的结果，而且差异程度较流感病毒感染后所表现的更为明显。同时，通过Ⅰ型干扰素对干扰素刺激应答元件(ISRE)的激活实验，我们发现ISRE的激活必须要有p53的存在才能够完全激活，这些结果均表明p53具有直接促进Ⅰ型干扰素通路激活的功能。p53启动子序列中被报道含有Ⅰ型干扰素作用元件，Ⅰ型干扰素可以转录调控p53的表达。而本研究发现p53具有直接促进Ⅰ型干扰素通路激活的功能。这表明p53与Ⅰ型干扰素可以相互促进、相互协调发挥抗病毒作用。
Ⅰ型干扰素在机体发挥抗流感过程中发挥着极其重要的作用。GBP1作为干扰素诱导的抗病毒蛋白已被报道可以抑制多种病毒的复制，但关于GBP1是否在流感病毒感染过程中发挥着抗病毒作用至今仍没有报道。最近，有报道发现流感病毒感染后GBP1的表达量显著上调。干扰素诱导的GBP1的表达可以被流感病毒抑制。这些研究结果表明GBP1与流感之间存在着一定的联系。本研究通过hGBP1的过表达实验证明了hGBP1具有抑制流感病毒复制的能力。hGBP1K51A的突变会使得hGBP1丧失其与GTP结合的能力，进而导致GTPase活性的丧失。hGBP1K51A的过表达不能够抑制流感病毒的复制，这表明GTPase活性是hGBP1发挥抑制流感病毒复制所必需的。NS1作为流感病毒拮抗宿主免疫反应的重要分子，可以与多类抗病毒蛋白直接结合，拮抗这些蛋白的抗病毒能力。我们研究发现NS1也可以和hGBP1相结合，NS1效应区123～144位氨基酸组成的片段与hGBP1第51位赖氨酸是两者相结合所必需的关键位点。GTPase是hGBP1发挥抗流感病毒的重要基础。那么NS1是否会抑制hGBP1的GTPase活性？研究发现NS1可以显著抑制hGBP1的GTPase活性，进而拮抗hGBP1介导的抗流感病毒能力。总之，流感病毒感染后，细胞的hGBP1在转录和蛋白水平上均显著上升。过表达hGBP1可以抑制流感病毒的复制。hGBP1第51位赖氨酸是hGBP1发挥抗流感作用所必需的。流感病毒NS1可以与hGBP1相结合，hGBP1第51位赖氨酸和NS1第123-144位氨基酸片段是两者发生结合所不可缺少的。NS1可以抑制hGBP1的GTPase活性，进而拮抗hGBP1发挥的抗病毒作用。hGBP1在机体发挥抗流感病毒免疫过程中具有着重要作用，流感病毒NS1可以显著拮抗这种抗病毒能力。
hGBP1被证明具有抑制流感病毒复制的能力。干扰素、IL-β及LPS等均可以诱导hGBP1的表达。p53作为一种转录因子，与干扰素通路具有着密切关系，p53已被报道可以转录调控多个干扰素诱导基因的表达。本实验室前期研究发现，流感病毒感染p53基因敲除小鼠后，GBP1的表达量明显低于p53野生型小鼠中GBP1的表达量。这表明GBP1与p53之间或许存在着一定的联系。通过ChIP on Chip进行高通量分析后，我们发现GBP1启动子序列能够和p53相结合。而进一步研究发现hGBP1的确为p53的靶基因。DNA损伤、病毒感染及细胞因子的刺激均可以通过影响p53而影响到hGBP1的表达。hGBP1启动子序列-4141～-4112和-2440～-2416两个基序为p53的结合反应元件。p53可以通过转录调控hGBP1的表达发挥抗病毒及抗肿瘤效应。该研究为进一步研究p53抗肿瘤和抗病毒的分子机制，以及开发抗病毒、抗肿瘤药物可以提供一定的参考依据。
总之，本研究证明了p53与Ⅰ型干扰素通路之间存在着紧密的联系，p53具有直接促进Ⅰ型干扰素通路激活的功能。p53与Ⅰ型干扰素可以相互促进、相互协调发挥抗流感病毒的作用。hGBP1被证明具有抑制流感病毒复制的能力，其为p53下游的靶基因。p53可以通过转录调控hGBP1的表达发挥抗病毒及抗肿瘤效应。这些研究结果，为今后进一步研究宿主的先天性抗流感病毒的反应机制，提高机体抗流感病毒能力提供了药物设计的靶标分子。为控制流感病毒在畜牧业中的危害提供理论基础，也为人类防治流感病毒的蔓延和扩散提供了一定的视角。
Tumor suppressor p53is widely known as ‘the guardian of the genome’, that performs importantfunctions in DNA repair process. In addition, p53has also been proven to regulate various biologicalprocesses such as cellular apoptosis, cell cycle arrest, cellular metabolism and antiviral responses.Influenza A virus (IAV) infection can induce the accumulation of p53, which results also in theupregulation of IRF9. The clinical symptoms, pathological responses and the viral loads of p53knockout (p53KO) mice shows much more severe than p53wildtype (p53WT) mice after IAV infection.All these results imply an important role of p53to perform antiviral activity against IAV infection.
A549cells with regular and deficient expression levels of p53were infected by IAV respectively. Theviral replication ability and the viral titers of the cells were determined and compared to understand theeffects of p53in IAV infection. Besides, the expression of several antiviral related genes in type Iinterferon (type I IFN) signaling pathway were detected to confirm that p53can affect the activation oftype I IFN signaling pathway during IAV infection. The results indicated that, p53directly affects theexpression of several antiviral related genes in type I IFN signaling pathway. Impaired expression ofantiviral related genes was found in the p53knockdown (p53KD) A549cells during IAV infection, suchas IRF9, IRF7, RIG-I, ISG20, ISG15, GBP1and OAS1. The IFN signaling pathway plays a key role inregulation of immune response against IAV infection，the results suggested that p53performs anti-IAVability through regulating the activation of type I IFN signaling pathway. To further prove the regulationof p53to type I IFN signaling pathway is an universal response, but not just in IAV infection cells. A549cells with regular and deficient expression levels of p53were treated with type I IFN, the expression ofseveral antiviral related genes in type I IFN signaling pathway were detected. In response to type I IFN,the impaired expression of antiviral related genes was also found in the p53KD cells, the impairedextent was more notable than the IAV infection groups. In addition, p53was found to be essential forthe activation of IFN-stimulated response elements (ISREs) induced by type I IFN. These resultsindicated p53can reinforce type I IFN signaling pathway. The promoter sequence of p53contains ISREfor type I IFN, so type I IFN can upregulate p53expression. Our results demonstrated p53can reinforcetype I IFN signaling pathway. It suggests a crosstalk between the p53and type I IFN pathway, p53andtype I IFN cooperates with each other to defend the cells from virus infection.
Type I IFN is indispensable for host to perform antiviral effects against IAV. GBP1has beenreported to possess the antiviral activity against several viruses. But whether IAV is inhibited by GBP1is still not clear. It is reported that, IAV infection induces GBP1expression, IAV inhibits the productionof GBP1induced by IFN. It suggests that GBP1may be involved in antiviral responses during IAVinfection. Overexpression of hGBP1was found to inhibit IAV replication in this study. The K51locatedin the highly conserved phosphate-binding loop of hGBP1is critical for its biological activity andfunction. Mutation of lysine51to alanine (K51A) abrogates GTP binding, dimerization, and GTPhydrolysis. Overexpression of hGBP1K51A failed to inhibit IAV replication, which suggests the GTPase of hGBP1is essential for its anti-IAV activity. NS1is widely known as an antagonist of hostimmune response to facilitate IAV replication. NS1was reported to interact with various anti-IAVproteins to antagonize their antiviral activity. NS1was also found to interact directly with hGBP1. Theresidues of123-144in the effector domain of NS1were required for the binding. The K51of hGBP1also decided the interaction. GTPase was proved to be essential for hGBP1to inhibit IAV replication;we predicted that NS1binds with hGBP1perhaps affects its GTPase activity. The ELIPA assay wascarried out to confirm this deduction, which showed the GTPase activity of hGBP1was significantlyimpaired by NS1. NS1clearly antagonized the anti-IAV activity of hGBP1. In conclusion, IAV infectiontriggers hGBP1expression. hGBP1possesses the anti-IAV activity, the GTPase of hGBP1is essentialfor its anti-IAV activity; the GTPase is dependent on the51K residue. NS1of IAV interacts with hGBP1,the51K of hGBP1and the residues of123-144of NS1are required for the interaction. NS1inhibits theGTPase of hGBP1to antagonize the anti-IAV activity of hGBP1. hGBP1shows an important effect inthe anti-IAV responses, NS1can weaken hGBP1-mediated anti-IAV ability.
Now, hGBP1is proved to possess anti-IAV activity. hGBP1expression can be induced by IFN, IL-βand LPS. p53, as a transcription factor shows important effect on IFN signaling pathway. Many ISGshave been proved to be p53transcriptional target genes. Our previous study showed that IAV infectioninduced GBP1expression was significantly impaired in p53KO mice compared with p53WT mice;which implied p53may correlate with GBP1expression. ChIP on Chip assay was carried out to identifythe potential transcriptional target genes of p53. The promoter sequence of GBP1was found to bindwith p53, and GBP1was identified as a potential target gene. We further confirmed that hGBP1is adirect transcriptional target gene of p53. DNA damage, viral infection and cytokines triggeredexpression of hGBP1was clearly regulated by p53. The fragments of-4141/-4112and-2440/-2416athGBP1promoter sequence were confirmed as the p53response elements. All these results indicated p53may transactivate hGBP1gene to perform the antiviral and antitumor activity. In conclusion, theseresults provided a new insight into antiviral and antitumor therapy and paved the way for future researchin p53functions.
In briefly, this study proved the correlation between p53and type I IFN pathway. p53possesses theability of enforcing type I IFN pathway activation. p53cooperates with type I IFN to perform anti-IAVresponses. hGBP1gene is a target gene of p53, p53upregulates hGBP1expression to carry out theantiviral and antitumor effects. Overall, all the results in this study provided a theoretical basis for hostanti-IAV immune responses research and anti-IAV strategies application to prevent the threat, damageand economic loss caused by IAV infection; which also offered several target molecules for anti-IAVmedicines development.
引文
1.姜恩平,范霓(2011).应用干扰素治疗肝炎研究进展.北华大学学报(自然科学版)(2):184-188.
2.李梵,陈国凤等.(2008).干扰素-治疗慢性乙型肝炎疗效预测因素的研究进展.解放军药学学报(6):525-528.
3.刘运龙,程远国等.(2008).干扰素研究进展.动物医学进展(2):85-89.
4.田硕,徐晨等.(2010).长效干扰素研究进展.中国生物工程杂志(5):122-127.
5.王礼凤,韩翠宁等.(2008).关于慢性乙型肝炎治疗的思考.湖南中医杂志(6):80-81.
6.王晓丽,王永明等.(2008).干扰素研究进展.动物医学进展(12):60-63.
7.叶智钊,黎敏英等.(2009).干扰素研究进展.畜牧与饲料科学(2):9-10
8. Abdullah, N. and B. Srinivasan, et al.(2009). Role of individual domains and identification ofinternal gap in human guanylate binding protein-1. J Mol Biol386(3):690-703.
9. Akira, S. and S. Uematsu, et al.(2006). Pathogen recognition and innate immunity. Cell124(4):783-801.
10. Albert, M. L. and B. Sauter, et al.(1998). Dendritic cells acquire antigen from apoptotic cells andinduce class I-restricted CTLs. Nature392(6671):86-9.
11. Baker, S. J. and E. R. Fearon, et al.(1989). Chromosome17deletions and p53gene mutations incolorectal carcinomas. Science244(4901):217-21.
12. Barbuddhe, S. B. and T. Chakraborty (2009). Listeria as an enteroinvasive gastrointestinalpathogen. Curr Top Microbiol Immunol337:173-95.
13. Bartee, E. and M. R. Mohamed, et al.(2008). Tumor necrosis factor and interferon: cytokines inharmony. Curr Opin Microbiol11(4):378-83.
14. Baudin, F. and I. Petit, et al.(2001). In vitro dissection of the membrane and RNP bindingactivities of influenza virus M1protein. Virology281(1):102-8.
15. Belardelli, F.(1995)."Role of interferons and other cytokines in the regulation of the immuneresponse." APMIS103(3):161-79.
16. Bonnet, S. and S. L. Archer, et al.(2007). A mitochondria-K+channel axis is suppressed in cancerand its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell11(1):37-51.
17. Boulo, S. and H. Akarsu, et al.(2007). Nuclear traffic of influenza virus proteins andribonucleoprotein complexes. Virus Res124(1-2):12-21.
18. Budanov, A. V. and A. A. Sablina, et al.(2004). Regeneration of peroxiredoxins by p53-regulatedsestrins, homologs of bacterial AhpD. Science304(5670):596-600.
19. Cano, C. E. and J. Gommeaux, et al.(2009). Tumor protein53-induced nuclear protein1is a majormediator of p53antioxidant function. Cancer Res69(1):219-26.
20. Caron, D. F. C. and E. Aberdam, et al.(2012).[The two faces of p63, Janus of the p53genefamily]. Med Sci (Paris)28(4):381-7.
21. Carter, C. C. and V. Y. Gorbacheva, et al.(2005). Inhibition of VSV and EMCV replication by theinterferon-induced GTPase, mGBP-2: differential requirement for wild-type GTP bindingdomain. Arch Virol150(6):1213-20.
22. Caux, C. and C. Massacrier, et al.(1994). Activation of human dendritic cells through CD40cross-linking. J Exp Med180(4):1263-72.
23. Chattergoon, M. A. and K. Muthumani, et al.(2008). DR5activation of caspase-8induces DCmaturation and immune enhancement in vivo. Mol Ther16(2):419-26.
24. Chen, W. and Z. Sun, et al.(2009). Direct interaction between Nrf2and p21(Cip1/WAF1)upregulates the Nrf2-mediated antioxidant response. Mol Cell34(6):663-73.
25. Cheng, Y. S. and C. E. Patterson, et al.(1991). Interferon-induced guanylate-binding proteins lackan N(T)KXD consensus motif and bind GMP in addition to GDP and GTP. Mol Cell Biol11(9):4717-25.
26. Christofk, H. R. and H. M. Vander, et al.(2008). The M2splice isoform of pyruvate kinase isimportant for cancer metabolism and tumour growth. Nature452(7184):230-3.
27. Clemens, M. J.(2003). Interferons and apoptosis. J Interferon Cytokine Res23(6):277-92.
28. Cros, J. F. and P. Palese (2003). Trafficking of viral genomic RNA into and out of the nucleus:influenza, Thogoto and Borna disease viruses. Virus Res95(1-2):3-12.
29. Da, S. R. and H. Langoni (2009). Toxoplasma gondii: host-parasite interaction and behaviormanipulation. Parasitol Res105(4):893-8.
30. Dafilis, M. P. and R. Moss, et al.(2012). Drivers and consequences of influenza antiviralresistant-strain emergence in a capacity-constrained pandemic response." Epidemics4(4):219-26.
31. de Veer, M. J. and M. Holko, et al.(2001)."Functional classification of interferon-stimulatedgenes identified using microarrays. J Leukoc Biol69(6):912-20.
32. Decker, T. and D. J. Lew, et al.(1991). Two distinct alpha-interferon-dependent signaltransduction pathways may contribute to activation of transcription of the guanylate-bindingprotein gene. Mol Cell Biol11(10):5147-53.
33. Degrandi, D. and C. Konermann, et al.(2007). Extensive characterization of IFN-induced GTPasesmGBP1to mGBP10involved in host defense. J Immunol179(11):7729-40.
34. Denko, N. C.(2008). Hypoxia, HIF1and glucose metabolism in the solid tumour. Nat Rev Cancer8(9):705-13.
35. Doms, R. W. and R. A. Lamb, et al.(1993). Folding and assembly of viral membrane proteins.Virology193(2):545-62.
36. Drane, P. and A. Bravard, et al.(2001). Reciprocal down-regulation of p53and SOD2geneexpression-implication in p53mediated apoptosis. Oncogene20(4):430-9.
37. Eliyahu, D. and A. Raz, et al.(1984). Participation of p53cellular tumour antigen intransformation of normal embryonic cells. Nature312(5995):646-9.
38. Eliyahu, D. and D. Michalovitz, et al.(1989). Wild-type p53can inhibit oncogene-mediated focusformation. Proc Natl Acad Sci U S A86(22):8763-7.
39. Fantin, V. R. and J. St-Pierre, et al.(2006). Attenuation of LDH-A expression uncovers a linkbetween glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell9(6):425-34.
40. Faraonio, R. and P. Vergara, et al.(2006). p53suppresses the Nrf2-dependent transcription ofantioxidant response genes. J Biol Chem281(52):39776-84.
41. Fellenberg, F. and T. B. Hartmann, et al.(2004). GBP-5splicing variants: New guanylate-bindingproteins with tumor-associated expression and antigenicity. J Invest Dermatol122(6):1510-7.
42. Fernandez-Sesma, A. and S. Marukian, et al.(2006). Influenza virus evades innate and adaptiveimmunity via the NS1protein. J Virol80(13):6295-304.
43. Finlay, C. A. and P. W. Hinds, et al.(1989). The p53proto-oncogene can act as a suppressor oftransformation. Cell57(7):1083-93.
44. Fortes, P. and A. Beloso, et al.(1994). Influenza virus NS1protein inhibits pre-mRNA splicingand blocks mRNA nucleocytoplasmic transport. EMBO J13(3):704-12.
45. Foster, S. L. and D. C. Hargreaves, et al.(2007). Gene-specific control of inflammation byTLR-induced chromatin modifications. Nature447(7147):972-8.
46. Fres, J. M. and S. Muller, et al.(2010). Purification of the CaaX-modified, dynamin-related largeGTPase hGBP1by coexpression with farnesyltransferase. J Lipid Res51(8):2454-9.
47. Gack, M. U. and R. A. Albrecht, et al.(2009). Influenza A virus NS1targets the ubiquitin ligaseTRIM25to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe5(5):439-49.
48. Garcia-Sastre, A.(2006). Antiviral response in pandemic influenza viruses. Emerg Infect Dis12(1):44-7.
49. Garcia-Sastre, A. and C. A. Biron (2006). Type1interferons and the virus-host relationship: alesson in detente. Science312(5775):879-82.
50. Geiss, G. K. and M. Salvatore, et al.(2002). Cellular transcriptional profiling in influenza Avirus-infected lung epithelial cells: the role of the nonstructural NS1protein in the evasion of thehost innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A99(16):10736-41.
51. Ghosh, A. and G. J. Praefcke, et al.(2006). How guanylate-binding proteins achieveassembly-stimulated processive cleavage of GTP to GMP. Nature440(7080):101-4.
52. Giannakopoulos, N. V. and E. Arutyunova, et al.(2009). ISG15Arg151and theISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. JVirol83(4):1602-10.
53. Gomez-Puertas, P. and C. Albo, et al.(2000). Influenza virus matrix protein is the major drivingforce in virus budding. J Virol74(24):11538-47.
54. Guenzi, E. and K. Topolt, et al.(2001). The helical domain of GBP-1mediates the inhibition ofendothelial cell proliferation by inflammatory cytokines. EMBO J20(20):5568-77.
55. Guenzi, E. and K. Topolt, et al.(2003). The guanylate binding protein-1GTPase controls theinvasive and angiogenic capability of endothelial cells through inhibition of MMP-1expression.EMBO J22(15):3772-82.
56. Hacke, K. and B. Rincon-Orozco, et al.(2010). Regulation of MCP-1chemokine transcription byp53. Mol Cancer9:82.
57. Hale, B. G. and R. E. Randall, et al.(2008). The multifunctional NS1protein of influenza Aviruses. J Gen Virol89(Pt10):2359-76.
58. Halevy, O. and D. Michalovitz, et al.(1990). Different tumor-derived p53mutants exhibit distinctbiological activities. Science250(4977):113-6.
59. Han, H. and Z. Q. Cui, et al.(2010). New regulatory mechanisms for the intracellular localizationand trafficking of influenza A virus NS1protein revealed by comparative analysis of A/PR/8/34and A/Sydney/5/97. J Gen Virol91(Pt12):2907-17.
60. Herbst-Kralovetz, M. and R. Pyles (2006). Toll-like receptors, innate immunity and HSVpathogenesis. Herpes13(2):37-41.
61. Honda, K. and S. Sakaguchi, et al.(2003). Selective contribution of IFN-alpha/beta signaling to thematuration of dendritic cells induced by double-stranded RNA or viral infection. Proc Natl AcadSci U S A100(19):10872-7.
62. Horn, H. F. and K. H. Vousden (2007). Coping with stress: multiple ways to activate p53.Oncogene26(9):1306-16.
63. Hsiang, T. Y. and C. Zhao, et al.(2009). Interferon-induced ISG15conjugation inhibits influenzaA virus gene expression and replication in human cells. J Virol83(12):5971-7.
64. Hsiao, N. W. and J. W. Chen, et al.(2010). ISG15over-expression inhibits replication of theJapanese encephalitis virus in human medulloblastoma cells. Antiviral Res85(3):504-11.
65. Hsu, P. P. and D. M. Sabatini (2008). Cancer cell metabolism: Warburg and beyond. Cell134(5):703-7.
66. Hsu, T. H. and C. C. Chu, et al.(2012). Expression of the class II tumor suppressor gene RIG1isdirectly regulated by p53tumor suppressor in cancer cell lines. FEBS Lett586(9):1287-93.
67. Hu, W. and C. Zhang, et al.(2010). Glutaminase2, a novel p53target gene regulating energymetabolism and antioxidant function. Proc Natl Acad Sci U S A107(16):7455-60.
68. Huang, X. and T. Liu, et al.(2001). Effect of influenza virus matrix protein and viral RNA onribonucleoprotein formation and nuclear export. Virology287(2):405-16.
69. Hughey, P. G. and P. C. Roberts, et al.(1995). Effects of antibody to the influenza A virus M2protein on M2surface expression and virus assembly. Virology212(2):411-21.
70. Hummer, B. T. and X. L. Li, et al.(2001). Role for p53in gene induction by double-stranded RNA.J Virol75(16):7774-7.
71. Hupp, T. R. and A. Sparks, et al.(1995). Small peptides activate the latent sequence-specific DNAbinding function of p53. Cell83(2):237-45.
72. Hussain, S. P. and P. Amstad, et al.(2004). p53-induced up-regulation of MnSOD and GPx but notcatalase increases oxidative stress and apoptosis. Cancer Res64(7):2350-6.
73. Imbeault, M. and M. Ouellet, et al.(2009). Microarray study reveals that HIV-1induces rapidtype-I interferon-dependent p53mRNA up-regulation in human primary CD4+T cells.Retrovirology6:5.
74. Indraccolo, S. and U. Pfeffer, et al.(2007). Identification of genes selectively regulated by IFNs inendothelial cells. J Immunol178(2):1122-35.
75. Inga, A. and F. Storici, et al.(2002). Differential transactivation by the p53transcription factor ishighly dependent on p53level and promoter target sequence. Mol Cell Biol22(24):8612-25.
76. Itsui, Y. and N. Sakamoto, et al.(2009). Antiviral effects of the interferon-induced proteinguanylate binding protein1and its interaction with the hepatitis C virus NS5B protein. Hepatology50(6):1727-37.
77. Jain, A. and C. A. Ison (2013). Chlamydia point-of-care testing: where are we now? Sex TransmInfect89(2):88-9.
78. Jebelli, J. D. and C. Hooper, et al.(2012). Emerging roles of p53in glial cell function in health anddisease. Glia60(4):515-25.
79. Jenkins, J. R. and K. Rudge, et al.(1984). Cellular immortalization by a cDNA clone encoding thetransformation-associated phosphoprotein p53. Nature312(5995):651-4.
80. Jenkins, J. R. and K. Rudge, et al.(1985). The cellular oncogene p53can be activated bymutagenesis. Nature317(6040):816-8.
81. Jeon, Y. J. and H. M. Yoo, et al.(2010). ISG15and immune diseases. Biochim Biophys Acta1802(5):485-96.
82. Jordan, J. J. and D. Menendez, et al.(2008). Noncanonical DNA motifs as transactivation targetsby wild type and mutant p53. PLoS Genet4(6): e1000104.
83. Kaisho, T. and S. Akira (2003). Regulation of dendritic cell function through toll-like receptors.Curr Mol Med3(8):759-71.
84. Kim, B. H. and A. R. Shenoy, et al.(2011). A family of IFN-gamma-inducible65-kD GTPasesprotects against bacterial infection. Science332(6030):717-21.
85. Kim, J. H. and J. K. Luo, et al.(2008). The level of hepatitis B virus replication is not affected byprotein ISG15modification but is reduced by inhibition of UBP43(USP18) expression. J Immunol181(9):6467-72.
86. Kochs, G. and O. Haller (1999). Interferon-induced human MxA GTPase blocks nuclear import ofThogoto virus nucleocapsids. Proc Natl Acad Sci U S A96(5):2082-6.
87. Kuang, Z. and E. J. Seo, et al.(2011). Mechanism of inhibition of retrovirus release from cells byinterferon-induced gene ISG15. J Virol85(14):7153-61.
88. Kumar, A. and F. S. Yu (2006). Toll-like receptors and corneal innate immunity. Curr Mol Med6(3):327-37.
89. Lai, C. and J. J. Struckhoff, et al.(2009). Mice lacking the ISG15E1enzyme UbE1L demonstrateincreased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection.J Virol83(2):1147-51.
90. Laliberte, J. and V. B. Carruthers (2008). Host cell manipulation by the human pathogenToxoplasma gondii. Cell Mol Life Sci65(12):1900-15.
91. Lane, D. P. and S. Benchimol (1990). p53: oncogene or anti-oncogene? Genes Dev4(1):1-8.
92. Latham, T. and J. M. Galarza (2001). Formation of wild-type and chimeric influenza virus-likeparticles following simultaneous expression of only four structural proteins. J Virol75(13):6154-65.
93. Le Bon, A. and N. Etchart, et al.(2003). Cross-priming of CD8+T cells stimulated byvirus-induced type I interferon. Nat Immunol4(10):1009-15.
94. Leng, J. and B. A. Butcher, et al.(2009). Dysregulation of macrophage signal transduction byToxoplasma gondii: past progress and recent advances. Parasite Immunol31(12):717-28.
95. Li, L. and D. Wang, et al.(2011). Crystal structure of human ISG15protein in complex withinfluenza B virus NS1B. J Biol Chem286(35):30258-62.
96. Li, S. and J. Y. Min, et al.(2006). Binding of the influenza A virus NS1protein to PKR mediatesthe inhibition of its activation by either PACT or double-stranded RNA. Virology349(1):13-21.
97. Li, Y. and H. Zhou, et al.(2011). Transcription analysis on response of swine lung to H1N1swineinfluenza virus. BMC Genomics12:398.
98. Lipnik, K. and E. Naschberger, et al.(2010). Interferon gamma-induced human guanylate bindingprotein1inhibits mammary tumor growth in mice. Mol Med16(5-6):177-87.
99. Liu, B. and Y. Chen, et al.(2008). ROS and p53: a versatile partnership. Free Radic Biol Med44(8):1529-35.
100. Liu, L. and I. Botos, et al.(2008). Structural basis of toll-like receptor3signaling withdouble-stranded RNA. Science320(5874):379-81.
101. Liu, Z. and H. Lu, et al.(2005). PUMA overexpression induces reactive oxygen species generationand proteasome-mediated stathmin degradation in colorectal cancer cells. Cancer Res65(5):1647-54.
102. Lu YP, W. B. D. J.(2007). Antiviral Effect of Interferon-Induced Guanylate Binding Protein-1against Coxsackie Virus and Hepatitis B Virus B3in Vitro. Virologica Sinica(3):193-198.
103. Lubeseder-Martellato, C. and E. Guenzi, et al.(2002). Guanylate-binding protein-1expression isselectively induced by inflammatory cytokines and is an activation marker of endothelial cellsduring inflammatory diseases. Am J Pathol161(5):1749-59.
104. Ma, B. and A. J. Levine (2007). Probing potential binding modes of the p53tetramer to DNAbased on the symmetries encoded in p53response elements. Nucleic Acids Res35(22):7733-47.
105. MacMicking, J. D.(2004). IFN-inducible GTPases and immunity to intracellular pathogens.Trends Immunol25(11):601-9.
106. Matlin, K. S. and H. Reggio, et al.(1981). Infectious entry pathway of influenza virus in a caninekidney cell line. J Cell Biol91(3Pt1):601-13.
107. Mercer, W. E. and C. Avignolo, et al.(1984). Role of the p53protein in cell proliferation asstudied by microinjection of monoclonal antibodies. Mol Cell Biol4(2):276-81.
108. Mibayashi, M. and L. Martinez-Sobrido, et al.(2007). Inhibition of retinoic acid-inducible geneI-mediated induction of beta interferon by the NS1protein of influenza A virus. J Virol81(2):514-24.
109. Milner, J. and E. A. Medcalf (1991). Cotranslation of activated mutant p53with wild type drivesthe wild-type p53protein into the mutant conformation. Cell65(5):765-74.
110. Milner, J. and F. McCormick (1980). Lymphocyte stimulation: concanavalin A induces theexpression of a53K protein. Cell Biol Int Rep4(7):663-7.
111. Min, J. Y. and S. Li, et al.(2007). A site on the influenza A virus NS1protein mediates bothinhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology363(1):236-43.
112. Mirpuri, J. and J. C. Brazil, et al.(2010). Commensal Escherichia coli reduces epithelial apoptosisthrough IFN-alphaA-mediated induction of guanylate binding protein-1in human and murinemodels of developing intestine. J Immunol184(12):7186-95.
113. Modiano, N. and Y. E. Lu, et al.(2005)."Golgi targeting of human guanylate-binding protein-1requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor." Proc NatlAcad Sci U S A102(24):8680-5.
114. Moore, E. C. and J. Barber, et al.(2008). Respiratory syncytial virus (RSV) attachment andnonstructural proteins modify the type I interferon response associated with suppressor of cytokinesignaling (SOCS) proteins and IFN-stimulated gene-15(ISG15). Virol J5:116.
115. Mori, T. and Y. Anazawa, et al.(2002). Identification of the interferon regulatory factor5gene(IRF-5) as a direct target for p53. Oncogene21(18):2914-8.
116. Moulder, J. W.(1991). Interaction of chlamydiae and host cells in vitro. Microbiol Rev55(1):143-90.
117. Mowat, M. and A. Cheng, et al.(1985). Rearrangements of the cellular p53gene inerythroleukaemic cells transformed by Friend virus. Nature314(6012):633-6.
118. Munoz-Fontela, C. and M. A. Garcia, et al.(2005). Resistance to viral infection of super p53mice.Oncogene24(18):3059-62.
119. Munoz-Fontela, C. and M. Pazos, et al.(2011). p53serves as a host antiviral factor that enhancesinnate and adaptive immune responses to influenza A virus. J Immunol187(12):6428-36.
120. Munoz-Fontela, C. and S. Macip, et al.(2008). Transcriptional role of p53in interferon-mediatedantiviral immunity. J Exp Med205(8):1929-38.
121. Munroe, D. G. and B. Rovinski, et al.(1988). Loss of a highly conserved domain on p53as a resultof gene deletion during Friend virus-induced erythroleukemia. Oncogene2(6):621-4.
122. Naschberger, E. and R. S. Croner, et al.(2008). Angiostatic immune reaction in colorectalcarcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer123(9):2120-9.
123. Naschberger, E. and T. Werner, et al.(2004). Nuclear factor-kappaB motif andinterferon-alpha-stimulated response element co-operate in the activation of guanylate-bindingprotein-1expression by inflammatory cytokines in endothelial cells. Biochem J379(Pt2):409-20.
124. Nayak, D. P. and E. K. Hui, et al.(2004). Assembly and budding of influenza virus. Virus Res106(2):147-65.
125. Nayak, D. P. and R. A. Balogun, et al.(2009). Influenza virus morphogenesis and budding. VirusRes143(2):147-61.
126. Neal, M. D. and C. P. Sodhi, et al.(2012). Toll-like receptor4is expressed on intestinal stem cellsand regulates their proliferation and apoptosis via the p53up-regulated modulator of apoptosis. JBiol Chem287(44):37296-308.
127. Nguyen, M. L. and R. M. Kraft, et al.(2007). p53and hTERT determine sensitivity to viralapoptosis. J Virol81(23):12985-95.
128. Nordmann, A. and L. Wixler, et al.(2012). A new splice variant of the human guanylate-bindingprotein3mediates anti-influenza activity through inhibition of viral transcription and replication.FASEB J26(3):1290-300.
129. Olszewski, M. A. and J. Gray, et al.(2006). In silico genomic analysis of the human and murineguanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res26(5):328-52.
130. Osada, M. and H. L. Park, et al.(2005). Differential recognition of response elements determinestarget gene specificity for p53and p63. Mol Cell Biol25(14):6077-89.
131. Osiak, A. and O. Utermohlen, et al.(2005). ISG15, an interferon-stimulated ubiquitin-like protein,is not essential for STAT1signaling and responses against vesicular stomatitis and lymphocyticchoriomeningitis virus. Mol Cell Biol25(15):6338-45.
132. Pammer, J. and C. Reinisch, et al.(2006). Interferon-alpha prevents apoptosis of endothelial cellsafter short-term exposure but induces replicative senescence after continuous stimulation. LabInvest86(10):997-1007.
133. Pampin, M. and Y. Simonin, et al.(2006). Cross talk between PML and p53during poliovirusinfection: implications for antiviral defense. J Virol80(17):8582-92.
134. Pan, W. and X. Zuo, et al.(2012). Guanylate-binding protein1participates in cellular antiviralresponse to dengue virus. Virol J9:292.
135. Parada, L. F. and H. Land, et al.(1984). Cooperation between gene encoding p53tumour antigenand ras in cellular transformation. Nature312(5995):649-51.
136. Pestka, S.(2003). A dance between interferon-alpha/beta and p53demonstrates collaborations intumor suppression and antiviral activities. Cancer Cell4(2):85-7.
137. Pestka, S. and J. A. Langer, et al.(1987). Interferons and their actions. Annu Rev Biochem56:727-77.
138. Petsch, B. and M. Schnee, et al.(2012). Protective efficacy of in vitro synthesized, specific mRNAvaccines against influenza A virus infection. Nat Biotechnol30(12):1210-6.
139. Pitha-Rowe, I. F. and P. M. Pitha (2007). Viral defense, carcinogenesis and ISG15: novel roles foran old ISG. Cytokine Growth Factor Rev18(5-6):409-17.
140. Pitini, V. and C. Arrigo, et al.(2010). How cells respond to interferons. J Clin Oncol28(25): e439;author reply e440.
141. Platanias, L. C. and E. N. Fish (1999). Signaling pathways activated by interferons. Exp Hematol27(11):1583-92.
142. Polyak, K. and Y. Xia, et al.(1997). A model for p53-induced apoptosis. Nature389(6648):300-5.
143. Pos, Z. and S. Selleri, et al.(2010). Genomic scale analysis of racial impact on response toIFN-alpha. Proc Natl Acad Sci U S A107(2):803-8.
144. Praefcke, G. J. and S. Kloep, et al.(2004). Identification of residues in the humanguanylate-binding protein1critical for nucleotide binding and cooperative GTP hydrolysis. JMol Biol344(1):257-69.
145. Prakash, B. and G. J. Praefcke, et al.(2000). Structure of human guanylate-binding protein1representing a unique class of GTP-binding proteins. Nature403(6769):567-71.
146. Prakash, B. and L. Renault, et al.(2000). Triphosphate structure of guanylate-binding protein1andimplications for nucleotide binding and GTPase mechanism. EMBO J19(17):4555-64.
147. Prives, C. and P. A. Hall (1999). The p53pathway. J Pathol187(1):112-26.
148. Puzio-Kuter, A. M.(2011). The Role of p53in Metabolic Regulation. Genes Cancer2(4):385-91.
149. Randall, R. E. and S. Goodbourn (2008). Interferons and viruses: an interplay between induction,signalling, antiviral responses and virus countermeasures. J Gen Virol89(Pt1):1-47.
150. Reich, N. C. and A. J. Levine (1984). Growth regulation of a cellular tumour antigen, p53, innontransformed cells. Nature308(5955):199-201.
151. Reid, A. H. and T. G. Fanning, et al.(2000). Characterization of the1918"Spanish" influenzavirus neuraminidase gene. Proc Natl Acad Sci U S A97(12):6785-90.
152. Reuter, S. and S. C. Gupta, et al.(2010). Oxidative stress, inflammation, and cancer: how are theylinked? Free Radic Biol Med49(11):1603-16.
153. Riley, T. and E. Sontag, et al.(2008). Transcriptional control of human p53-regulated genes. NatRev Mol Cell Biol9(5):402-12.
154. Rivas, C. and S. A. Aaronson, et al.(2010). Dual Role of p53in Innate Antiviral Immunity.Viruses2(1):298-313.
155. Rivera, A. and S. A. Maxwell (2005). The p53-induced gene-6(proline oxidase) mediatesapoptosis through a calcineurin-dependent pathway. J Biol Chem280(32):29346-54.
156. Roan, N. R. and M. N. Starnbach (2008). Immune-mediated control of Chlamydia infection. CellMicrobiol10(1):9-19.
157. Roberts, P. C. and R. A. Lamb, et al.(1998). The M1and M2proteins of influenza A virus areimportant determinants in filamentous particle formation. Virology240(1):127-37.
158. Rodier, F. and J. Campisi, et al.(2007). Two faces of p53: aging and tumor suppression. NucleicAcids Res35(22):7475-84.
159. Sadler, A. J. and B. R. Williams (2008). Interferon-inducible antiviral effectors. Nat Rev Immunol8(7):559-68.
160. Sage, L. K. and J. M. Fox, et al.(2013). Subsisting H1N1Influenza Memory Responses areInsufficient to Protect from Pandemic H1N1Influenza Challenge in C57BL/6Mice. J Gen Virol.
161. Salomon, R. and P. Staeheli, et al.(2007). Mx1gene protects mice against the highly lethal humanH5N1influenza virus. Cell Cycle6(19):2417-21.
162. Schmitt, A. P. and R. A. Lamb (2005). Influenza virus assembly and budding at the viral budozone.Adv Virus Res64:383-416.
163. Schnoor, M. and A. Betanzos, et al.(2009). Guanylate-binding protein-1is expressed at tightjunctions of intestinal epithelial cells in response to interferon-gamma and regulates barrierfunction through effects on apoptosis. Mucosal Immunol2(1):33-42.
164. Schoggins, J. W. and S. J. Wilson, et al.(2011). A diverse range of gene products are effectors ofthe type I interferon antiviral response. Nature472(7344):481-5.
165. Schroeder, C. and H. Heider, et al.(2005). The influenza virus ion channel and maturation cofactorM2is a cholesterol-binding protein. Eur Biophys J34(1):52-66.
166. Sen, G. C. and S. N. Sarkar (2007). The interferon-stimulated genes: targets of direct signaling byinterferons, double-stranded RNA, and viruses. Curr Top Microbiol Immunol316:233-50.
167. Shakya, A. and R. Cooksey, et al.(2009). Oct1loss of function induces a coordinate metabolicshift that opposes tumorigenicity. Nat Cell Biol11(3):320-7.
168. Shen, Y. and X. Wang, et al.(2009). Influenza A virus induces p53accumulation in a biphasicpattern. Biochem Biophys Res Commun382(2):331-5.
169. Skaug, B. and Z. J. Chen (2010). Emerging role of ISG15in antiviral immunity. Cell143(2):187-90.
170. Smith, M. L. and M. A. Kumar (2010). The "Two faces" of Tumor Suppressor p53-revisited. MolCell Pharmacol2(3):117-119.
171. Son, K. N. and S. Pugazhenthi, et al.(2009). Activation of tumor suppressor protein p53isrequired for Theiler's murine encephalomyelitis virus-induced apoptosis in M1-D macrophages. JVirol83(20):10770-7.
172. Stark, G. R. and I. M. Kerr, et al.(1998). How cells respond to interferons. Annu Rev Biochem67:227-64.
173. Stickney, J. T. and J. E. Buss (2000). Murine guanylate-binding protein: incomplete geranylgeranylisoprenoid modification of an interferon-gamma-inducible guanosine triphosphate-binding protein.Mol Biol Cell11(7):2191-200.
174. Su, W. C. and W. L. Liu, et al.(2009). Ribavirin enhances interferon signaling via stimulation ofmTOR and p53activities. FEBS Lett583(17):2793-8.
175. Takahashi, T. and M. M. Nau, et al.(1989). p53: a frequent target for genetic abnormalities in lungcancer. Science246(4929):491-4.
176. Takahasi, K. and H. Kumeta, et al.(2009). Solution structures of cytosolic RNA sensor MDA5andLGP2C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors. JBiol Chem284(26):17465-74.
177. Takaoka, A. and H. Yanai, et al.(2005). Integral role of IRF-5in the gene induction programmeactivated by Toll-like receptors. Nature434(7030):243-9.
178. Takaoka, A. and S. Hayakawa, et al.(2003). Integration of interferon-alpha/beta signalling to p53responses in tumour suppression and antiviral defence. Nature424(6948):516-23.
179. Tan, M. and S. Li, et al.(1999). Transcriptional activation of the human glutathione peroxidasepromoter by p53. J Biol Chem274(17):12061-6.
180. Taubenberger, J. K. and J. V. Hultin, et al.(2007). Discovery and characterization of the1918pandemic influenza virus in historical context. Antivir Ther12(4Pt B):581-91.
181. Taura, M. and A. Eguma, et al.(2008). p53regulates Toll-like receptor3expression and functionin human epithelial cell lines. Mol Cell Biol28(21):6557-67.
182. Thomas, R. and L. Kaplan, et al.(1983). Characterization of human p53antigens employingprimate specific monoclonal antibodies. Virology131(2):502-17.
183. Tietzel, I. and C. El-Haibi, et al.(2009). Human guanylate binding proteins potentiate theanti-chlamydia effects of interferon-gamma. PLoS One4(8): e6499.
184. Tipping, P. G.(2006). Toll-like receptors: the interface between innate and adaptive immunity. JAm Soc Nephrol17(7):1769-71.
185. Toyoda, T. and Y. Asano, et al.(1995). Role of GTPase activity of murine Mx1protein in nuclearlocalization and anti-influenza virus activity. J Gen Virol76(Pt7):1867-9.
186. Trinei, M. and M. Giorgio, et al.(2002). A p53-p66Shc signalling pathway controls intracellularredox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene21(24):3872-8.
187. Tripal, P. and M. Bauer, et al.(2007). Unique features of different members of the humanguanylate-binding protein family. J Interferon Cytokine Res27(1):44-52.
188. Tsai, F. M. and R. Y. Shyu, et al.(2007). RIG1suppresses Ras activation and induces cellularapoptosis at the Golgi apparatus. Cell Signal19(5):989-99.
189. Tumpey, T. M. and K. J. Szretter, et al.(2007). The Mx1gene protects mice against the pandemic1918and highly lethal human H5N1influenza viruses. J Virol81(19):10818-21.
190. Turpin, E. and K. Luke, et al.(2005). Influenza virus infection increases p53activity: role of p53in cell death and viral replication. J Virol79(14):8802-11.
191. Uematsu, S. and S. Akira (2006). Toll-like receptors and innate immunity. J Mol Med (Berl)84(9):712-25.
192. van den Broek, M. F. and U. Muller, et al.(1995). Immune defence in mice lacking type I and/ortype II interferon receptors. Immunol Rev148:5-18.
193. Vestal, D. J. and J. A. Jeyaratnam (2011). The guanylate-binding proteins: emerging insights intothe biochemical properties and functions of this family of large interferon-induced guanosinetriphosphatase. J Interferon Cytokine Res31(1):89-97.
194. Virreira, W. S. and W. Niedelman, et al.(2011). Determinants of GBP recruitment to Toxoplasmagondii vacuoles and the parasitic factors that control it. PLoS One6(9): e24434.
195. Vogelstein, B. and D. Lane, et al.(2000). Surfing the p53network. Nature408(6810):307-10.
196. Vogelstein, B. and E. R. Fearon, et al.(1988). Genetic alterations during colorectal-tumordevelopment. N Engl J Med319(9):525-32.
197. Vopel, T. and A. Syguda, et al.(2010). Mechanism of GTPase-activity-induced self-assembly ofhuman guanylate binding protein1. J Mol Biol400(1):63-70.
198. Vousden, K. H. and C. Prives (2009). Blinded by the Light: The Growing Complexity of p53. Cell137(3):413-31.
199. Vousden, K. H. and D. P. Lane (2007). p53in health and disease. Nat Rev Mol Cell Biol8(4):275-83.
200. Vousden, K. H. and K. M. Ryan (2009). p53and metabolism. Nat Rev Cancer9(10):691-700.
201. Wang, B. and Z. Xiao, et al.(2009). Redefining the p53response element. Proc Natl Acad Sci U SA106(34):14373-8.
202. Wang, X. and X. Deng, et al.(2012). Stabilization of p53in influenza A virus-infected cells isassociated with compromised MDM2-mediated ubiquitination of p53. J Biol Chem287(22):18366-75.
203. Wang, X. and Y. Shen, et al.(2010). The non-structural (NS1) protein of influenza A virusassociates with p53and inhibits p53-mediated transcriptional activity and apoptosis. BiochemBiophys Res Commun395(1):141-5.
204. Weinlander, K. and E. Naschberger, et al.(2008). Guanylate binding protein-1inhibits spreadingand migration of endothelial cells through induction of integrin alpha4expression. FASEB J22(12):4168-78.
205. Whittaker, G. R.(2001). Intracellular trafficking of influenza virus: clinical implications formolecular medicine. Expert Rev Mol Med2001:1-13.
206. Yanai, H. and H. M. Chen, et al.(2007). Role of IFN regulatory factor5transcription factor inantiviral immunity and tumor suppression. Proc Natl Acad Sci U S A104(9):3402-7.
207. Yoon, C. H. and E. S. Lee, et al.(2009). PKR, a p53target gene, plays a crucial role in thetumor-suppressor function of p53. Proc Natl Acad Sci U S A106(19):7852-7.
208. Yoon, K. A. and Y. Nakamura, et al.(2004). Identification of ALDH4as a p53-inducible gene andits protective role in cellular stresses. J Hum Genet49(3):134-40.
209. Yuan, W. and R. M. Krug (2001). Influenza B virus NS1protein inhibits conjugation of theinterferon (IFN)-induced ubiquitin-like ISG15protein. EMBO J20(3):362-71.
210. Zaslavsky, L. and Y. Bao, et al.(2008). Visualization of large influenza virus sequence datasetsusing adaptively aggregated trees with sampling-based subscale representation. BMCBioinformatics9:237.
211. Zhang, D. and D. E. Zhang (2011). Interferon-stimulated gene15and the protein ISGylationsystem. J Interferon Cytokine Res31(1):119-30.
212. Zhao, C. and C. Denison, et al.(2005). Human ISG15conjugation targets both IFN-induced andconstitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U SA102(29):10200-5.
213. Zhao, C. and T. Y. Hsiang, et al.(2010). ISG15conjugation system targets the viral NS1protein ininfluenza A virus-infected cells. Proc Natl Acad Sci U S A107(5):2253-8.
2.李梵,陈国凤等.(2008).干扰素-治疗慢性乙型肝炎疗效预测因素的研究进展.解放军药学学报(6):525-528.
3.刘运龙,程远国等.(2008).干扰素研究进展.动物医学进展(2):85-89.
4.田硕,徐晨等.(2010).长效干扰素研究进展.中国生物工程杂志(5):122-127.
5.王礼凤,韩翠宁等.(2008).关于慢性乙型肝炎治疗的思考.湖南中医杂志(6):80-81.
6.王晓丽,王永明等.(2008).干扰素研究进展.动物医学进展(12):60-63.
7.叶智钊,黎敏英等.(2009).干扰素研究进展.畜牧与饲料科学(2):9-10
8. Abdullah, N. and B. Srinivasan, et al.(2009). Role of individual domains and identification ofinternal gap in human guanylate binding protein-1. J Mol Biol386(3):690-703.
9. Akira, S. and S. Uematsu, et al.(2006). Pathogen recognition and innate immunity. Cell124(4):783-801.
10. Albert, M. L. and B. Sauter, et al.(1998). Dendritic cells acquire antigen from apoptotic cells andinduce class I-restricted CTLs. Nature392(6671):86-9.
11. Baker, S. J. and E. R. Fearon, et al.(1989). Chromosome17deletions and p53gene mutations incolorectal carcinomas. Science244(4901):217-21.
12. Barbuddhe, S. B. and T. Chakraborty (2009). Listeria as an enteroinvasive gastrointestinalpathogen. Curr Top Microbiol Immunol337:173-95.
13. Bartee, E. and M. R. Mohamed, et al.(2008). Tumor necrosis factor and interferon: cytokines inharmony. Curr Opin Microbiol11(4):378-83.
14. Baudin, F. and I. Petit, et al.(2001). In vitro dissection of the membrane and RNP bindingactivities of influenza virus M1protein. Virology281(1):102-8.
15. Belardelli, F.(1995)."Role of interferons and other cytokines in the regulation of the immuneresponse." APMIS103(3):161-79.
16. Bonnet, S. and S. L. Archer, et al.(2007). A mitochondria-K+channel axis is suppressed in cancerand its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell11(1):37-51.
17. Boulo, S. and H. Akarsu, et al.(2007). Nuclear traffic of influenza virus proteins andribonucleoprotein complexes. Virus Res124(1-2):12-21.
18. Budanov, A. V. and A. A. Sablina, et al.(2004). Regeneration of peroxiredoxins by p53-regulatedsestrins, homologs of bacterial AhpD. Science304(5670):596-600.
19. Cano, C. E. and J. Gommeaux, et al.(2009). Tumor protein53-induced nuclear protein1is a majormediator of p53antioxidant function. Cancer Res69(1):219-26.
20. Caron, D. F. C. and E. Aberdam, et al.(2012).[The two faces of p63, Janus of the p53genefamily]. Med Sci (Paris)28(4):381-7.
21. Carter, C. C. and V. Y. Gorbacheva, et al.(2005). Inhibition of VSV and EMCV replication by theinterferon-induced GTPase, mGBP-2: differential requirement for wild-type GTP bindingdomain. Arch Virol150(6):1213-20.
22. Caux, C. and C. Massacrier, et al.(1994). Activation of human dendritic cells through CD40cross-linking. J Exp Med180(4):1263-72.
23. Chattergoon, M. A. and K. Muthumani, et al.(2008). DR5activation of caspase-8induces DCmaturation and immune enhancement in vivo. Mol Ther16(2):419-26.
24. Chen, W. and Z. Sun, et al.(2009). Direct interaction between Nrf2and p21(Cip1/WAF1)upregulates the Nrf2-mediated antioxidant response. Mol Cell34(6):663-73.
25. Cheng, Y. S. and C. E. Patterson, et al.(1991). Interferon-induced guanylate-binding proteins lackan N(T)KXD consensus motif and bind GMP in addition to GDP and GTP. Mol Cell Biol11(9):4717-25.
26. Christofk, H. R. and H. M. Vander, et al.(2008). The M2splice isoform of pyruvate kinase isimportant for cancer metabolism and tumour growth. Nature452(7184):230-3.
27. Clemens, M. J.(2003). Interferons and apoptosis. J Interferon Cytokine Res23(6):277-92.
28. Cros, J. F. and P. Palese (2003). Trafficking of viral genomic RNA into and out of the nucleus:influenza, Thogoto and Borna disease viruses. Virus Res95(1-2):3-12.
29. Da, S. R. and H. Langoni (2009). Toxoplasma gondii: host-parasite interaction and behaviormanipulation. Parasitol Res105(4):893-8.
30. Dafilis, M. P. and R. Moss, et al.(2012). Drivers and consequences of influenza antiviralresistant-strain emergence in a capacity-constrained pandemic response." Epidemics4(4):219-26.
31. de Veer, M. J. and M. Holko, et al.(2001)."Functional classification of interferon-stimulatedgenes identified using microarrays. J Leukoc Biol69(6):912-20.
32. Decker, T. and D. J. Lew, et al.(1991). Two distinct alpha-interferon-dependent signaltransduction pathways may contribute to activation of transcription of the guanylate-bindingprotein gene. Mol Cell Biol11(10):5147-53.
33. Degrandi, D. and C. Konermann, et al.(2007). Extensive characterization of IFN-induced GTPasesmGBP1to mGBP10involved in host defense. J Immunol179(11):7729-40.
34. Denko, N. C.(2008). Hypoxia, HIF1and glucose metabolism in the solid tumour. Nat Rev Cancer8(9):705-13.
35. Doms, R. W. and R. A. Lamb, et al.(1993). Folding and assembly of viral membrane proteins.Virology193(2):545-62.
36. Drane, P. and A. Bravard, et al.(2001). Reciprocal down-regulation of p53and SOD2geneexpression-implication in p53mediated apoptosis. Oncogene20(4):430-9.
37. Eliyahu, D. and A. Raz, et al.(1984). Participation of p53cellular tumour antigen intransformation of normal embryonic cells. Nature312(5995):646-9.
38. Eliyahu, D. and D. Michalovitz, et al.(1989). Wild-type p53can inhibit oncogene-mediated focusformation. Proc Natl Acad Sci U S A86(22):8763-7.
39. Fantin, V. R. and J. St-Pierre, et al.(2006). Attenuation of LDH-A expression uncovers a linkbetween glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell9(6):425-34.
40. Faraonio, R. and P. Vergara, et al.(2006). p53suppresses the Nrf2-dependent transcription ofantioxidant response genes. J Biol Chem281(52):39776-84.
41. Fellenberg, F. and T. B. Hartmann, et al.(2004). GBP-5splicing variants: New guanylate-bindingproteins with tumor-associated expression and antigenicity. J Invest Dermatol122(6):1510-7.
42. Fernandez-Sesma, A. and S. Marukian, et al.(2006). Influenza virus evades innate and adaptiveimmunity via the NS1protein. J Virol80(13):6295-304.
43. Finlay, C. A. and P. W. Hinds, et al.(1989). The p53proto-oncogene can act as a suppressor oftransformation. Cell57(7):1083-93.
44. Fortes, P. and A. Beloso, et al.(1994). Influenza virus NS1protein inhibits pre-mRNA splicingand blocks mRNA nucleocytoplasmic transport. EMBO J13(3):704-12.
45. Foster, S. L. and D. C. Hargreaves, et al.(2007). Gene-specific control of inflammation byTLR-induced chromatin modifications. Nature447(7147):972-8.
46. Fres, J. M. and S. Muller, et al.(2010). Purification of the CaaX-modified, dynamin-related largeGTPase hGBP1by coexpression with farnesyltransferase. J Lipid Res51(8):2454-9.
47. Gack, M. U. and R. A. Albrecht, et al.(2009). Influenza A virus NS1targets the ubiquitin ligaseTRIM25to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe5(5):439-49.
48. Garcia-Sastre, A.(2006). Antiviral response in pandemic influenza viruses. Emerg Infect Dis12(1):44-7.
49. Garcia-Sastre, A. and C. A. Biron (2006). Type1interferons and the virus-host relationship: alesson in detente. Science312(5775):879-82.
50. Geiss, G. K. and M. Salvatore, et al.(2002). Cellular transcriptional profiling in influenza Avirus-infected lung epithelial cells: the role of the nonstructural NS1protein in the evasion of thehost innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A99(16):10736-41.
51. Ghosh, A. and G. J. Praefcke, et al.(2006). How guanylate-binding proteins achieveassembly-stimulated processive cleavage of GTP to GMP. Nature440(7080):101-4.
52. Giannakopoulos, N. V. and E. Arutyunova, et al.(2009). ISG15Arg151and theISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. JVirol83(4):1602-10.
53. Gomez-Puertas, P. and C. Albo, et al.(2000). Influenza virus matrix protein is the major drivingforce in virus budding. J Virol74(24):11538-47.
54. Guenzi, E. and K. Topolt, et al.(2001). The helical domain of GBP-1mediates the inhibition ofendothelial cell proliferation by inflammatory cytokines. EMBO J20(20):5568-77.
55. Guenzi, E. and K. Topolt, et al.(2003). The guanylate binding protein-1GTPase controls theinvasive and angiogenic capability of endothelial cells through inhibition of MMP-1expression.EMBO J22(15):3772-82.
56. Hacke, K. and B. Rincon-Orozco, et al.(2010). Regulation of MCP-1chemokine transcription byp53. Mol Cancer9:82.
57. Hale, B. G. and R. E. Randall, et al.(2008). The multifunctional NS1protein of influenza Aviruses. J Gen Virol89(Pt10):2359-76.
58. Halevy, O. and D. Michalovitz, et al.(1990). Different tumor-derived p53mutants exhibit distinctbiological activities. Science250(4977):113-6.
59. Han, H. and Z. Q. Cui, et al.(2010). New regulatory mechanisms for the intracellular localizationand trafficking of influenza A virus NS1protein revealed by comparative analysis of A/PR/8/34and A/Sydney/5/97. J Gen Virol91(Pt12):2907-17.
60. Herbst-Kralovetz, M. and R. Pyles (2006). Toll-like receptors, innate immunity and HSVpathogenesis. Herpes13(2):37-41.
61. Honda, K. and S. Sakaguchi, et al.(2003). Selective contribution of IFN-alpha/beta signaling to thematuration of dendritic cells induced by double-stranded RNA or viral infection. Proc Natl AcadSci U S A100(19):10872-7.
62. Horn, H. F. and K. H. Vousden (2007). Coping with stress: multiple ways to activate p53.Oncogene26(9):1306-16.
63. Hsiang, T. Y. and C. Zhao, et al.(2009). Interferon-induced ISG15conjugation inhibits influenzaA virus gene expression and replication in human cells. J Virol83(12):5971-7.
64. Hsiao, N. W. and J. W. Chen, et al.(2010). ISG15over-expression inhibits replication of theJapanese encephalitis virus in human medulloblastoma cells. Antiviral Res85(3):504-11.
65. Hsu, P. P. and D. M. Sabatini (2008). Cancer cell metabolism: Warburg and beyond. Cell134(5):703-7.
66. Hsu, T. H. and C. C. Chu, et al.(2012). Expression of the class II tumor suppressor gene RIG1isdirectly regulated by p53tumor suppressor in cancer cell lines. FEBS Lett586(9):1287-93.
67. Hu, W. and C. Zhang, et al.(2010). Glutaminase2, a novel p53target gene regulating energymetabolism and antioxidant function. Proc Natl Acad Sci U S A107(16):7455-60.
68. Huang, X. and T. Liu, et al.(2001). Effect of influenza virus matrix protein and viral RNA onribonucleoprotein formation and nuclear export. Virology287(2):405-16.
69. Hughey, P. G. and P. C. Roberts, et al.(1995). Effects of antibody to the influenza A virus M2protein on M2surface expression and virus assembly. Virology212(2):411-21.
70. Hummer, B. T. and X. L. Li, et al.(2001). Role for p53in gene induction by double-stranded RNA.J Virol75(16):7774-7.
71. Hupp, T. R. and A. Sparks, et al.(1995). Small peptides activate the latent sequence-specific DNAbinding function of p53. Cell83(2):237-45.
72. Hussain, S. P. and P. Amstad, et al.(2004). p53-induced up-regulation of MnSOD and GPx but notcatalase increases oxidative stress and apoptosis. Cancer Res64(7):2350-6.
73. Imbeault, M. and M. Ouellet, et al.(2009). Microarray study reveals that HIV-1induces rapidtype-I interferon-dependent p53mRNA up-regulation in human primary CD4+T cells.Retrovirology6:5.
74. Indraccolo, S. and U. Pfeffer, et al.(2007). Identification of genes selectively regulated by IFNs inendothelial cells. J Immunol178(2):1122-35.
75. Inga, A. and F. Storici, et al.(2002). Differential transactivation by the p53transcription factor ishighly dependent on p53level and promoter target sequence. Mol Cell Biol22(24):8612-25.
76. Itsui, Y. and N. Sakamoto, et al.(2009). Antiviral effects of the interferon-induced proteinguanylate binding protein1and its interaction with the hepatitis C virus NS5B protein. Hepatology50(6):1727-37.
77. Jain, A. and C. A. Ison (2013). Chlamydia point-of-care testing: where are we now? Sex TransmInfect89(2):88-9.
78. Jebelli, J. D. and C. Hooper, et al.(2012). Emerging roles of p53in glial cell function in health anddisease. Glia60(4):515-25.
79. Jenkins, J. R. and K. Rudge, et al.(1984). Cellular immortalization by a cDNA clone encoding thetransformation-associated phosphoprotein p53. Nature312(5995):651-4.
80. Jenkins, J. R. and K. Rudge, et al.(1985). The cellular oncogene p53can be activated bymutagenesis. Nature317(6040):816-8.
81. Jeon, Y. J. and H. M. Yoo, et al.(2010). ISG15and immune diseases. Biochim Biophys Acta1802(5):485-96.
82. Jordan, J. J. and D. Menendez, et al.(2008). Noncanonical DNA motifs as transactivation targetsby wild type and mutant p53. PLoS Genet4(6): e1000104.
83. Kaisho, T. and S. Akira (2003). Regulation of dendritic cell function through toll-like receptors.Curr Mol Med3(8):759-71.
84. Kim, B. H. and A. R. Shenoy, et al.(2011). A family of IFN-gamma-inducible65-kD GTPasesprotects against bacterial infection. Science332(6030):717-21.
85. Kim, J. H. and J. K. Luo, et al.(2008). The level of hepatitis B virus replication is not affected byprotein ISG15modification but is reduced by inhibition of UBP43(USP18) expression. J Immunol181(9):6467-72.
86. Kochs, G. and O. Haller (1999). Interferon-induced human MxA GTPase blocks nuclear import ofThogoto virus nucleocapsids. Proc Natl Acad Sci U S A96(5):2082-6.
87. Kuang, Z. and E. J. Seo, et al.(2011). Mechanism of inhibition of retrovirus release from cells byinterferon-induced gene ISG15. J Virol85(14):7153-61.
88. Kumar, A. and F. S. Yu (2006). Toll-like receptors and corneal innate immunity. Curr Mol Med6(3):327-37.
89. Lai, C. and J. J. Struckhoff, et al.(2009). Mice lacking the ISG15E1enzyme UbE1L demonstrateincreased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection.J Virol83(2):1147-51.
90. Laliberte, J. and V. B. Carruthers (2008). Host cell manipulation by the human pathogenToxoplasma gondii. Cell Mol Life Sci65(12):1900-15.
91. Lane, D. P. and S. Benchimol (1990). p53: oncogene or anti-oncogene? Genes Dev4(1):1-8.
92. Latham, T. and J. M. Galarza (2001). Formation of wild-type and chimeric influenza virus-likeparticles following simultaneous expression of only four structural proteins. J Virol75(13):6154-65.
93. Le Bon, A. and N. Etchart, et al.(2003). Cross-priming of CD8+T cells stimulated byvirus-induced type I interferon. Nat Immunol4(10):1009-15.
94. Leng, J. and B. A. Butcher, et al.(2009). Dysregulation of macrophage signal transduction byToxoplasma gondii: past progress and recent advances. Parasite Immunol31(12):717-28.
95. Li, L. and D. Wang, et al.(2011). Crystal structure of human ISG15protein in complex withinfluenza B virus NS1B. J Biol Chem286(35):30258-62.
96. Li, S. and J. Y. Min, et al.(2006). Binding of the influenza A virus NS1protein to PKR mediatesthe inhibition of its activation by either PACT or double-stranded RNA. Virology349(1):13-21.
97. Li, Y. and H. Zhou, et al.(2011). Transcription analysis on response of swine lung to H1N1swineinfluenza virus. BMC Genomics12:398.
98. Lipnik, K. and E. Naschberger, et al.(2010). Interferon gamma-induced human guanylate bindingprotein1inhibits mammary tumor growth in mice. Mol Med16(5-6):177-87.
99. Liu, B. and Y. Chen, et al.(2008). ROS and p53: a versatile partnership. Free Radic Biol Med44(8):1529-35.
100. Liu, L. and I. Botos, et al.(2008). Structural basis of toll-like receptor3signaling withdouble-stranded RNA. Science320(5874):379-81.
101. Liu, Z. and H. Lu, et al.(2005). PUMA overexpression induces reactive oxygen species generationand proteasome-mediated stathmin degradation in colorectal cancer cells. Cancer Res65(5):1647-54.
102. Lu YP, W. B. D. J.(2007). Antiviral Effect of Interferon-Induced Guanylate Binding Protein-1against Coxsackie Virus and Hepatitis B Virus B3in Vitro. Virologica Sinica(3):193-198.
103. Lubeseder-Martellato, C. and E. Guenzi, et al.(2002). Guanylate-binding protein-1expression isselectively induced by inflammatory cytokines and is an activation marker of endothelial cellsduring inflammatory diseases. Am J Pathol161(5):1749-59.
104. Ma, B. and A. J. Levine (2007). Probing potential binding modes of the p53tetramer to DNAbased on the symmetries encoded in p53response elements. Nucleic Acids Res35(22):7733-47.
105. MacMicking, J. D.(2004). IFN-inducible GTPases and immunity to intracellular pathogens.Trends Immunol25(11):601-9.
106. Matlin, K. S. and H. Reggio, et al.(1981). Infectious entry pathway of influenza virus in a caninekidney cell line. J Cell Biol91(3Pt1):601-13.
107. Mercer, W. E. and C. Avignolo, et al.(1984). Role of the p53protein in cell proliferation asstudied by microinjection of monoclonal antibodies. Mol Cell Biol4(2):276-81.
108. Mibayashi, M. and L. Martinez-Sobrido, et al.(2007). Inhibition of retinoic acid-inducible geneI-mediated induction of beta interferon by the NS1protein of influenza A virus. J Virol81(2):514-24.
109. Milner, J. and E. A. Medcalf (1991). Cotranslation of activated mutant p53with wild type drivesthe wild-type p53protein into the mutant conformation. Cell65(5):765-74.
110. Milner, J. and F. McCormick (1980). Lymphocyte stimulation: concanavalin A induces theexpression of a53K protein. Cell Biol Int Rep4(7):663-7.
111. Min, J. Y. and S. Li, et al.(2007). A site on the influenza A virus NS1protein mediates bothinhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology363(1):236-43.
112. Mirpuri, J. and J. C. Brazil, et al.(2010). Commensal Escherichia coli reduces epithelial apoptosisthrough IFN-alphaA-mediated induction of guanylate binding protein-1in human and murinemodels of developing intestine. J Immunol184(12):7186-95.
113. Modiano, N. and Y. E. Lu, et al.(2005)."Golgi targeting of human guanylate-binding protein-1requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor." Proc NatlAcad Sci U S A102(24):8680-5.
114. Moore, E. C. and J. Barber, et al.(2008). Respiratory syncytial virus (RSV) attachment andnonstructural proteins modify the type I interferon response associated with suppressor of cytokinesignaling (SOCS) proteins and IFN-stimulated gene-15(ISG15). Virol J5:116.
115. Mori, T. and Y. Anazawa, et al.(2002). Identification of the interferon regulatory factor5gene(IRF-5) as a direct target for p53. Oncogene21(18):2914-8.
116. Moulder, J. W.(1991). Interaction of chlamydiae and host cells in vitro. Microbiol Rev55(1):143-90.
117. Mowat, M. and A. Cheng, et al.(1985). Rearrangements of the cellular p53gene inerythroleukaemic cells transformed by Friend virus. Nature314(6012):633-6.
118. Munoz-Fontela, C. and M. A. Garcia, et al.(2005). Resistance to viral infection of super p53mice.Oncogene24(18):3059-62.
119. Munoz-Fontela, C. and M. Pazos, et al.(2011). p53serves as a host antiviral factor that enhancesinnate and adaptive immune responses to influenza A virus. J Immunol187(12):6428-36.
120. Munoz-Fontela, C. and S. Macip, et al.(2008). Transcriptional role of p53in interferon-mediatedantiviral immunity. J Exp Med205(8):1929-38.
121. Munroe, D. G. and B. Rovinski, et al.(1988). Loss of a highly conserved domain on p53as a resultof gene deletion during Friend virus-induced erythroleukemia. Oncogene2(6):621-4.
122. Naschberger, E. and R. S. Croner, et al.(2008). Angiostatic immune reaction in colorectalcarcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer123(9):2120-9.
123. Naschberger, E. and T. Werner, et al.(2004). Nuclear factor-kappaB motif andinterferon-alpha-stimulated response element co-operate in the activation of guanylate-bindingprotein-1expression by inflammatory cytokines in endothelial cells. Biochem J379(Pt2):409-20.
124. Nayak, D. P. and E. K. Hui, et al.(2004). Assembly and budding of influenza virus. Virus Res106(2):147-65.
125. Nayak, D. P. and R. A. Balogun, et al.(2009). Influenza virus morphogenesis and budding. VirusRes143(2):147-61.
126. Neal, M. D. and C. P. Sodhi, et al.(2012). Toll-like receptor4is expressed on intestinal stem cellsand regulates their proliferation and apoptosis via the p53up-regulated modulator of apoptosis. JBiol Chem287(44):37296-308.
127. Nguyen, M. L. and R. M. Kraft, et al.(2007). p53and hTERT determine sensitivity to viralapoptosis. J Virol81(23):12985-95.
128. Nordmann, A. and L. Wixler, et al.(2012). A new splice variant of the human guanylate-bindingprotein3mediates anti-influenza activity through inhibition of viral transcription and replication.FASEB J26(3):1290-300.
129. Olszewski, M. A. and J. Gray, et al.(2006). In silico genomic analysis of the human and murineguanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res26(5):328-52.
130. Osada, M. and H. L. Park, et al.(2005). Differential recognition of response elements determinestarget gene specificity for p53and p63. Mol Cell Biol25(14):6077-89.
131. Osiak, A. and O. Utermohlen, et al.(2005). ISG15, an interferon-stimulated ubiquitin-like protein,is not essential for STAT1signaling and responses against vesicular stomatitis and lymphocyticchoriomeningitis virus. Mol Cell Biol25(15):6338-45.
132. Pammer, J. and C. Reinisch, et al.(2006). Interferon-alpha prevents apoptosis of endothelial cellsafter short-term exposure but induces replicative senescence after continuous stimulation. LabInvest86(10):997-1007.
133. Pampin, M. and Y. Simonin, et al.(2006). Cross talk between PML and p53during poliovirusinfection: implications for antiviral defense. J Virol80(17):8582-92.
134. Pan, W. and X. Zuo, et al.(2012). Guanylate-binding protein1participates in cellular antiviralresponse to dengue virus. Virol J9:292.
135. Parada, L. F. and H. Land, et al.(1984). Cooperation between gene encoding p53tumour antigenand ras in cellular transformation. Nature312(5995):649-51.
136. Pestka, S.(2003). A dance between interferon-alpha/beta and p53demonstrates collaborations intumor suppression and antiviral activities. Cancer Cell4(2):85-7.
137. Pestka, S. and J. A. Langer, et al.(1987). Interferons and their actions. Annu Rev Biochem56:727-77.
138. Petsch, B. and M. Schnee, et al.(2012). Protective efficacy of in vitro synthesized, specific mRNAvaccines against influenza A virus infection. Nat Biotechnol30(12):1210-6.
139. Pitha-Rowe, I. F. and P. M. Pitha (2007). Viral defense, carcinogenesis and ISG15: novel roles foran old ISG. Cytokine Growth Factor Rev18(5-6):409-17.
140. Pitini, V. and C. Arrigo, et al.(2010). How cells respond to interferons. J Clin Oncol28(25): e439;author reply e440.
141. Platanias, L. C. and E. N. Fish (1999). Signaling pathways activated by interferons. Exp Hematol27(11):1583-92.
142. Polyak, K. and Y. Xia, et al.(1997). A model for p53-induced apoptosis. Nature389(6648):300-5.
143. Pos, Z. and S. Selleri, et al.(2010). Genomic scale analysis of racial impact on response toIFN-alpha. Proc Natl Acad Sci U S A107(2):803-8.
144. Praefcke, G. J. and S. Kloep, et al.(2004). Identification of residues in the humanguanylate-binding protein1critical for nucleotide binding and cooperative GTP hydrolysis. JMol Biol344(1):257-69.
145. Prakash, B. and G. J. Praefcke, et al.(2000). Structure of human guanylate-binding protein1representing a unique class of GTP-binding proteins. Nature403(6769):567-71.
146. Prakash, B. and L. Renault, et al.(2000). Triphosphate structure of guanylate-binding protein1andimplications for nucleotide binding and GTPase mechanism. EMBO J19(17):4555-64.
147. Prives, C. and P. A. Hall (1999). The p53pathway. J Pathol187(1):112-26.
148. Puzio-Kuter, A. M.(2011). The Role of p53in Metabolic Regulation. Genes Cancer2(4):385-91.
149. Randall, R. E. and S. Goodbourn (2008). Interferons and viruses: an interplay between induction,signalling, antiviral responses and virus countermeasures. J Gen Virol89(Pt1):1-47.
150. Reich, N. C. and A. J. Levine (1984). Growth regulation of a cellular tumour antigen, p53, innontransformed cells. Nature308(5955):199-201.
151. Reid, A. H. and T. G. Fanning, et al.(2000). Characterization of the1918"Spanish" influenzavirus neuraminidase gene. Proc Natl Acad Sci U S A97(12):6785-90.
152. Reuter, S. and S. C. Gupta, et al.(2010). Oxidative stress, inflammation, and cancer: how are theylinked? Free Radic Biol Med49(11):1603-16.
153. Riley, T. and E. Sontag, et al.(2008). Transcriptional control of human p53-regulated genes. NatRev Mol Cell Biol9(5):402-12.
154. Rivas, C. and S. A. Aaronson, et al.(2010). Dual Role of p53in Innate Antiviral Immunity.Viruses2(1):298-313.
155. Rivera, A. and S. A. Maxwell (2005). The p53-induced gene-6(proline oxidase) mediatesapoptosis through a calcineurin-dependent pathway. J Biol Chem280(32):29346-54.
156. Roan, N. R. and M. N. Starnbach (2008). Immune-mediated control of Chlamydia infection. CellMicrobiol10(1):9-19.
157. Roberts, P. C. and R. A. Lamb, et al.(1998). The M1and M2proteins of influenza A virus areimportant determinants in filamentous particle formation. Virology240(1):127-37.
158. Rodier, F. and J. Campisi, et al.(2007). Two faces of p53: aging and tumor suppression. NucleicAcids Res35(22):7475-84.
159. Sadler, A. J. and B. R. Williams (2008). Interferon-inducible antiviral effectors. Nat Rev Immunol8(7):559-68.
160. Sage, L. K. and J. M. Fox, et al.(2013). Subsisting H1N1Influenza Memory Responses areInsufficient to Protect from Pandemic H1N1Influenza Challenge in C57BL/6Mice. J Gen Virol.
161. Salomon, R. and P. Staeheli, et al.(2007). Mx1gene protects mice against the highly lethal humanH5N1influenza virus. Cell Cycle6(19):2417-21.
162. Schmitt, A. P. and R. A. Lamb (2005). Influenza virus assembly and budding at the viral budozone.Adv Virus Res64:383-416.
163. Schnoor, M. and A. Betanzos, et al.(2009). Guanylate-binding protein-1is expressed at tightjunctions of intestinal epithelial cells in response to interferon-gamma and regulates barrierfunction through effects on apoptosis. Mucosal Immunol2(1):33-42.
164. Schoggins, J. W. and S. J. Wilson, et al.(2011). A diverse range of gene products are effectors ofthe type I interferon antiviral response. Nature472(7344):481-5.
165. Schroeder, C. and H. Heider, et al.(2005). The influenza virus ion channel and maturation cofactorM2is a cholesterol-binding protein. Eur Biophys J34(1):52-66.
166. Sen, G. C. and S. N. Sarkar (2007). The interferon-stimulated genes: targets of direct signaling byinterferons, double-stranded RNA, and viruses. Curr Top Microbiol Immunol316:233-50.
167. Shakya, A. and R. Cooksey, et al.(2009). Oct1loss of function induces a coordinate metabolicshift that opposes tumorigenicity. Nat Cell Biol11(3):320-7.
168. Shen, Y. and X. Wang, et al.(2009). Influenza A virus induces p53accumulation in a biphasicpattern. Biochem Biophys Res Commun382(2):331-5.
169. Skaug, B. and Z. J. Chen (2010). Emerging role of ISG15in antiviral immunity. Cell143(2):187-90.
170. Smith, M. L. and M. A. Kumar (2010). The "Two faces" of Tumor Suppressor p53-revisited. MolCell Pharmacol2(3):117-119.
171. Son, K. N. and S. Pugazhenthi, et al.(2009). Activation of tumor suppressor protein p53isrequired for Theiler's murine encephalomyelitis virus-induced apoptosis in M1-D macrophages. JVirol83(20):10770-7.
172. Stark, G. R. and I. M. Kerr, et al.(1998). How cells respond to interferons. Annu Rev Biochem67:227-64.
173. Stickney, J. T. and J. E. Buss (2000). Murine guanylate-binding protein: incomplete geranylgeranylisoprenoid modification of an interferon-gamma-inducible guanosine triphosphate-binding protein.Mol Biol Cell11(7):2191-200.
174. Su, W. C. and W. L. Liu, et al.(2009). Ribavirin enhances interferon signaling via stimulation ofmTOR and p53activities. FEBS Lett583(17):2793-8.
175. Takahashi, T. and M. M. Nau, et al.(1989). p53: a frequent target for genetic abnormalities in lungcancer. Science246(4929):491-4.
176. Takahasi, K. and H. Kumeta, et al.(2009). Solution structures of cytosolic RNA sensor MDA5andLGP2C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors. JBiol Chem284(26):17465-74.
177. Takaoka, A. and H. Yanai, et al.(2005). Integral role of IRF-5in the gene induction programmeactivated by Toll-like receptors. Nature434(7030):243-9.
178. Takaoka, A. and S. Hayakawa, et al.(2003). Integration of interferon-alpha/beta signalling to p53responses in tumour suppression and antiviral defence. Nature424(6948):516-23.
179. Tan, M. and S. Li, et al.(1999). Transcriptional activation of the human glutathione peroxidasepromoter by p53. J Biol Chem274(17):12061-6.
180. Taubenberger, J. K. and J. V. Hultin, et al.(2007). Discovery and characterization of the1918pandemic influenza virus in historical context. Antivir Ther12(4Pt B):581-91.
181. Taura, M. and A. Eguma, et al.(2008). p53regulates Toll-like receptor3expression and functionin human epithelial cell lines. Mol Cell Biol28(21):6557-67.
182. Thomas, R. and L. Kaplan, et al.(1983). Characterization of human p53antigens employingprimate specific monoclonal antibodies. Virology131(2):502-17.
183. Tietzel, I. and C. El-Haibi, et al.(2009). Human guanylate binding proteins potentiate theanti-chlamydia effects of interferon-gamma. PLoS One4(8): e6499.
184. Tipping, P. G.(2006). Toll-like receptors: the interface between innate and adaptive immunity. JAm Soc Nephrol17(7):1769-71.
185. Toyoda, T. and Y. Asano, et al.(1995). Role of GTPase activity of murine Mx1protein in nuclearlocalization and anti-influenza virus activity. J Gen Virol76(Pt7):1867-9.
186. Trinei, M. and M. Giorgio, et al.(2002). A p53-p66Shc signalling pathway controls intracellularredox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene21(24):3872-8.
187. Tripal, P. and M. Bauer, et al.(2007). Unique features of different members of the humanguanylate-binding protein family. J Interferon Cytokine Res27(1):44-52.
188. Tsai, F. M. and R. Y. Shyu, et al.(2007). RIG1suppresses Ras activation and induces cellularapoptosis at the Golgi apparatus. Cell Signal19(5):989-99.
189. Tumpey, T. M. and K. J. Szretter, et al.(2007). The Mx1gene protects mice against the pandemic1918and highly lethal human H5N1influenza viruses. J Virol81(19):10818-21.
190. Turpin, E. and K. Luke, et al.(2005). Influenza virus infection increases p53activity: role of p53in cell death and viral replication. J Virol79(14):8802-11.
191. Uematsu, S. and S. Akira (2006). Toll-like receptors and innate immunity. J Mol Med (Berl)84(9):712-25.
192. van den Broek, M. F. and U. Muller, et al.(1995). Immune defence in mice lacking type I and/ortype II interferon receptors. Immunol Rev148:5-18.
193. Vestal, D. J. and J. A. Jeyaratnam (2011). The guanylate-binding proteins: emerging insights intothe biochemical properties and functions of this family of large interferon-induced guanosinetriphosphatase. J Interferon Cytokine Res31(1):89-97.
194. Virreira, W. S. and W. Niedelman, et al.(2011). Determinants of GBP recruitment to Toxoplasmagondii vacuoles and the parasitic factors that control it. PLoS One6(9): e24434.
195. Vogelstein, B. and D. Lane, et al.(2000). Surfing the p53network. Nature408(6810):307-10.
196. Vogelstein, B. and E. R. Fearon, et al.(1988). Genetic alterations during colorectal-tumordevelopment. N Engl J Med319(9):525-32.
197. Vopel, T. and A. Syguda, et al.(2010). Mechanism of GTPase-activity-induced self-assembly ofhuman guanylate binding protein1. J Mol Biol400(1):63-70.
198. Vousden, K. H. and C. Prives (2009). Blinded by the Light: The Growing Complexity of p53. Cell137(3):413-31.
199. Vousden, K. H. and D. P. Lane (2007). p53in health and disease. Nat Rev Mol Cell Biol8(4):275-83.
200. Vousden, K. H. and K. M. Ryan (2009). p53and metabolism. Nat Rev Cancer9(10):691-700.
201. Wang, B. and Z. Xiao, et al.(2009). Redefining the p53response element. Proc Natl Acad Sci U SA106(34):14373-8.
202. Wang, X. and X. Deng, et al.(2012). Stabilization of p53in influenza A virus-infected cells isassociated with compromised MDM2-mediated ubiquitination of p53. J Biol Chem287(22):18366-75.
203. Wang, X. and Y. Shen, et al.(2010). The non-structural (NS1) protein of influenza A virusassociates with p53and inhibits p53-mediated transcriptional activity and apoptosis. BiochemBiophys Res Commun395(1):141-5.
204. Weinlander, K. and E. Naschberger, et al.(2008). Guanylate binding protein-1inhibits spreadingand migration of endothelial cells through induction of integrin alpha4expression. FASEB J22(12):4168-78.
205. Whittaker, G. R.(2001). Intracellular trafficking of influenza virus: clinical implications formolecular medicine. Expert Rev Mol Med2001:1-13.
206. Yanai, H. and H. M. Chen, et al.(2007). Role of IFN regulatory factor5transcription factor inantiviral immunity and tumor suppression. Proc Natl Acad Sci U S A104(9):3402-7.
207. Yoon, C. H. and E. S. Lee, et al.(2009). PKR, a p53target gene, plays a crucial role in thetumor-suppressor function of p53. Proc Natl Acad Sci U S A106(19):7852-7.
208. Yoon, K. A. and Y. Nakamura, et al.(2004). Identification of ALDH4as a p53-inducible gene andits protective role in cellular stresses. J Hum Genet49(3):134-40.
209. Yuan, W. and R. M. Krug (2001). Influenza B virus NS1protein inhibits conjugation of theinterferon (IFN)-induced ubiquitin-like ISG15protein. EMBO J20(3):362-71.
210. Zaslavsky, L. and Y. Bao, et al.(2008). Visualization of large influenza virus sequence datasetsusing adaptively aggregated trees with sampling-based subscale representation. BMCBioinformatics9:237.
211. Zhang, D. and D. E. Zhang (2011). Interferon-stimulated gene15and the protein ISGylationsystem. J Interferon Cytokine Res31(1):119-30.
212. Zhao, C. and C. Denison, et al.(2005). Human ISG15conjugation targets both IFN-induced andconstitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U SA102(29):10200-5.
213. Zhao, C. and T. Y. Hsiang, et al.(2010). ISG15conjugation system targets the viral NS1protein ininfluenza A virus-infected cells. Proc Natl Acad Sci U S A107(5):2253-8.