Crosstalk between STAT2 and Bim in type I IFN Signaling

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。

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.