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.

概括 I 型干扰素 (IFN-/) 疗法的抗肿瘤功效是可变的，因为它可以诱导任一肿瘤细胞生长抑制或凋亡。 I 型 IFN 诱导细胞凋亡的潜在分子机制仍然存在很大程度上不为人知。定义 I 型干扰素激活导致肿瘤细胞破坏的信号传导途径具有重要意义。临床重要性。我们的初步数据表明 STAT2 的缺陷会阻止细胞接受 IFN- -诱导的细胞凋亡，并且这种缺陷与干扰素刺激基因（ISG）的表达受损有关。我们发现促凋亡蛋白 Bim 会破坏线粒体的完整性，并被 I 型干扰素激活 STAT2依赖的方式。重要的是，Bim 和 STAT2 信号之间的串扰可能存在，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 活性调节仅通过调节 BH3 结构域 Bcl-2 的促凋亡活性来实现线粒体依赖性死亡途径蛋白质。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 I 型药物的信号传导机制和抗肿瘤功效 IFN 诱导的细胞凋亡受 STAT2 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）

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 刺激基因表达中的重要作用。

DOI：
发表时间：
2014-10
期刊：
影响因子：
5.5
作者：
Sheikh, Faruk;Dickensheets, Harold;Gamero, Ana M;Vogel, Stefanie N;Donnelly, Raymond P
通讯作者：
Donnelly, Raymond P

Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis.

Stat2 缺失会导致 LPS 诱导的脓毒症中不依赖于细胞因子的细胞介导的致死性。

DOI：
发表时间：
2013-05-21
期刊：
影响因子：
11.1
作者：
Alazawi, William;Heath, Helen;Waters, Jennifer A;Woodfin, Abigail;O'Brien, Alastair J;Scarzello, Anthony J;Ma, Bin;Lopez;Jacobs, Michael;Petts, Gemma;Goldin, Robert D;Nourshargh, Sussan;Gamero, Ana M;Foster, Graham R
通讯作者：
Foster, Graham R

Interferons as inducers of apoptosis in malignant cells.

干扰素作为恶性细胞凋亡的诱导剂。

DOI：
发表时间：
2013-04
期刊：
影响因子：
0
作者：
Kotredes, Kevin P;Gamero, Ana M
通讯作者：
Gamero, Ana M

Host STAT2/type I interferon axis controls tumor growth.

宿主 STAT2/I 型干扰素轴控制肿瘤生长。

DOI：
发表时间：
2015-01-01
期刊：
影响因子：
6.4
作者：
Yue, Chanyu;Xu, Jun;Tan Estioko, Marc Daryl;Kotredes, Kevin P;Lopez;Hilliard, Brendan A;Baker, Darren P;Gallucci, Stefania;Gamero, Ana M
通讯作者：
Gamero, Ana M

Interferon-lambda as a potential therapeutic agent in cancer treatment.

干扰素-λ 作为癌症治疗的潜在治疗剂。