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

基本信息

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
项目类别：
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

项目摘要

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-α/β）疗法的抗肿瘤功效是可变的，因为它可以诱导肿瘤细胞生长抑制或细胞凋亡。 I 型 IFN 诱导细胞凋亡的潜在分子机制仍然很大程度上未知。定义 I 型干扰素激活导致肿瘤细胞破坏的信号通路具有临床意义。我们的初步数据表明，STAT2 的缺陷可阻止细胞经历 IFN-α 诱导的细胞凋亡，并且这种缺陷与干扰素刺激基因 (ISG) 的表达受损相关。我们发现促凋亡蛋白 Bim 会破坏线粒体完整性，并以 STAT2 依赖性方式被 I 型 IFN 激活。重要的是，Bim 和 STAT2 信号之间可能存在串扰，因为缺乏 Bim 或 STAT2 的小鼠胚胎成纤维细胞中 I 型 IFN 的凋亡活性受损。根据我们的数据，我们的假设是，I 型 IFN 诱导的 STAT2 活性通过调节仅 BH3 结构域的 Bcl-2 蛋白的促凋亡活性来调节线粒体依赖性死亡途径的激活。具体目标： 1) 确定 STAT2 调节 Bim 激活的机制。 2) 表征 STAT2 中的保守残基并确定它们是否调节 I 型 IFN 信号传导和 Bim 激活。 3) 确定 I 型 IFN 的体内抗肿瘤作用如何需要 STAT2。意义：这些结果将有助于深入了解 STAT2 和 Bim 调节的 I 型 IFN 诱导的细胞凋亡的信号传导机制和抗肿瘤功效。公共卫生相关性：干扰素是一类可溶性蛋白质，以其抗病毒宿主防御和细胞生长抑制的功能而闻名。 STAT2 是介导 IFN 抗病毒作用所需的关键分子，但对其在癌症中的功能作用知之甚少。我们的项目将研究干扰素限制肿瘤生长的分子机制。