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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：
8464654
负责人：
ANA M GAMERO
金额：
$ 25.54万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464654
关键词：
Address Affect Antiviral Agents Apoptosis Apoptotic BCL-2 Protein 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 I型干扰素（IFN-γ）治疗的抗肿瘤疗效是可变的，因为它可以诱导肿瘤细胞，生长抑制或凋亡。I型干扰素诱导细胞凋亡的潜在分子机制仍然存在大部分未知。定义由I型IFN激活的导致肿瘤细胞破坏的信号通路如下：临床重要性我们的初步数据表明，STAT 2的缺陷会阻止细胞接受IFN-γ治疗。 - 诱导的细胞凋亡，这种缺陷与干扰素刺激基因（ISG）的表达受损相关。我们已经发现，促凋亡蛋白Bim，破坏线粒体的完整性，被激活的I型干扰素， STAT 2依赖性。重要的是，Bim和STAT 2信号之间可能存在串扰，因为在Bim或STAT 2缺陷的小鼠胚胎成纤维细胞中，I型IFN的凋亡活性受损。基于我们的数据，我们的假设是I型IFN诱导的STAT 2活性调节了线粒体依赖性死亡途径通过仅调节BH 3结构域的促凋亡活性Bcl-2 proteins. 具体目的：1）确定STAT 2调节Bim活化的机制。2)表征 STAT 2中的保守残基，并确定它们是否调节I型IFN信号传导和Bim活化。第三章确定STAT 2是如何在体内I型干扰素的抗肿瘤作用所需的。意义：这些结果将为深入了解I型抗肿瘤药物的信号转导机制和抗肿瘤疗效提供依据。 IFN诱导的细胞凋亡受STAT 2和Bim调节。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Host STAT2/type I interferon axis controls tumor growth.

DOI：
10.1002/ijc.29004
发表时间：
2015-01-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Yue, Chanyu;Xu, Jun;Estioko, Marc Daryl Tan;Kotredes, Kevin P.;Lopez-Otalora, Yolanda;Hilliard, Brendan A.;Baker, Darren P.;Gallucci, Stefania;Gamero, Ana M.
通讯作者：
Gamero, Ana M.

An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages.

IFN-β 在巨噬细胞中 LPS 诱导 IFN 刺激的基因表达中发挥重要作用。