Crosstalk between STAT2 and Bim in type I IFN Signaling

I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰

• 批准号: 8073617
• 负责人: ANA M GAMERO
• 金额: $ 27.17万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073617
• 关键词: Address; Affect; Antiviral Agents; Apoptosis; Apoptotic; BH3 Domain; Cell Line; Cells; Cessation of life; Clinical; Complex; DNA Binding Domain; Data; Defect; Embryo; Event; Failure; Family; Family member; Fibroblasts; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Host Defense; Interferon Type I; Interferons; Laboratories; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mitochondria; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasm Transplantation; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Protein-Serine-Threonine Kinases; Proteins; Role; STAT1 gene; STAT2 gene; Signal Pathway; Signal Transduction; Site; Skin Carcinoma; Testing; base; cell growth; cytokine; in vivo; insight; interferon therapy; member; neoplastic cell; novel; prevent; pro-apoptotic protein; src Homology Region 2 Domain; tumor; tumor growth

DESCRIPTION (provided by applicant): The antitumor efficacy of type I interferon (IFN-?/?) therapy is variable since it can induce either tumor cell growth inhibition or apoptosis. The underlying molecular mechanisms of type I IFN-induced apoptosis remain largely unknown. Defining the signaling pathways activated by type I IFNs leading to tumor cell destruction are of clinical importance. Our preliminary data indicates that a deficiency in STAT2 prevents cells from undergoing IFN-?-induced apoptosis and this defect correlates with impaired expression of interferon stimulated genes (ISGs). We have found that the pro-apoptotic protein Bim, which disrupts mitochondrial integrity, is activated by type I IFNs in a STAT2-dependent manner. Importantly, crosstalk between Bim and STAT2 signals likely exists since the apoptotic activity of type I IFNs is impaired in mouse embryonic fibroblasts deficient in either Bim or STAT2. Based on our data, our hypothesis is that type I IFN-induced STAT2 activity regulates the activation of the mitochondrial dependent death pathway by modulating the pro-apoptotic activities of BH3 domain only Bcl-2 proteins. Specific Aims: 1) Determine the mechanism by which STAT2 modulates Bim activation. 2) Characterize conserved residues in STAT2 and determine whether they modulate type I IFN signaling and Bim activation. 3) Determine how STAT2 is required for the in vivo antitumor effects of type I IFNs. Significance: These results will provide insights into the signaling mechanisms and antitumor efficacy of type I IFN-induced apoptosis that are regulated by STAT2 and Bim. PUBLIC HEALTH RELEVANCE: Interferons are a family of soluble proteins that are known for their function in antiviral host defense and cell growth inhibition. STAT2 is a critical molecule required for mediating the antiviral effects of IFN but little is known about its functional role in cancer. Our project will address a molecular mechanism by which interferons restrict tumor growth.

描述（由申请人提供）：I型干扰素（IFN- /?）治疗的抗肿瘤效果是可变的，因为它可以诱导肿瘤细胞生长抑制或凋亡。I型ifn诱导细胞凋亡的潜在分子机制在很大程度上仍然未知。明确I型ifn激活导致肿瘤细胞破坏的信号通路具有重要的临床意义。我们的初步数据表明STAT2的缺乏会阻止细胞发生IFN-？这种缺陷与干扰素刺激基因（ISGs）的表达受损有关。我们发现，破坏线粒体完整性的促凋亡蛋白Bim被I型ifn以依赖stat2的方式激活。重要的是，Bim和STAT2信号之间可能存在串扰，因为在缺乏Bim或STAT2的小鼠胚胎成纤维细胞中，I型ifn的凋亡活性受损。