Crosstalk between STAT2 and Bim in type I IFN Signaling

摘要 I型干扰素(干扰素)治疗的抗肿瘤效果是不同的，因为它可以诱导任何一种肿瘤细胞 生长抑制或细胞凋亡。I型干扰素诱导细胞凋亡的潜在分子机制仍然存在 很大程度上是未知的。定义由I型IFN激活的导致肿瘤细胞破坏的信号通路是 临床重要性。我们的初步数据表明，STAT2的缺陷阻止细胞接受干扰素- 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激活 依赖于STAT2的方式。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活性调节STAT2的激活 仅通过调节BH3结构域的促凋亡活性实现线粒体依赖的死亡途径 蛋白质。 具体目的：1)确定STAT2调节BIM激活的机制。2)描述 STAT2中的保守残基，并确定它们是否调制I型干扰素信号和Bim激活。3) 确定I型IFN的体内抗肿瘤效应需要STAT2的方式。 意义：这些结果将为深入了解I型病毒的信号机制和抗肿瘤效果提供依据。 受STAT2和Bim调控的干扰素诱导的细胞凋亡。

Summary 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.