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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：
8253486
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/8253486
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 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

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.

总结