Crosstalk between STAT2 and Bim in type I IFN Signaling

描述(申请人提供)：I型干扰素(干扰素)的抗肿瘤效果治疗方法多种多样，因为它既可以诱导肿瘤细胞生长抑制，也可以诱导细胞凋亡。I型干扰素诱导细胞凋亡的潜在分子机制在很大程度上仍不清楚。明确I型干扰素激活的信号通路导致肿瘤细胞破坏具有临床意义。我们的初步数据表明，STAT2的缺陷阻止了细胞经历干扰素诱导的凋亡，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是由I型IFN以STAT2依赖的方式激活的。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的凋亡活性受到损害。 根据我们的数据，我们的假设是，I型干扰素诱导的STAT2活性通过调节BH3结构域仅有的Bcl-2蛋白的促凋亡活性来调节线粒体依赖死亡途径的激活。 具体目的：1)确定STAT2调节BIM激活的机制。2)鉴定STAT2中的保守残基，并确定它们是否调节I型干扰素信号转导和Bim激活。3)确定I型IFN的体内抗肿瘤作用需要STAT2。 意义：这些结果将为深入了解由STAT2和Bim调控的I型干扰素诱导的细胞凋亡的信号机制和抗肿瘤效果提供见解。 与公共健康相关：干扰素是一类可溶性蛋白质，以其在抗病毒宿主防御和细胞生长抑制方面的功能而闻名。STAT2是介导干扰素抗病毒作用的关键分子，但对其在癌症中的作用知之甚少。我们的项目将解决干扰素限制肿瘤生长的分子机制。

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.