CYTOKINE SIGNALING

细胞因子信号转导

• 批准号: 2444909
• 负责人: OSCAR R COLAMONICI
• 金额: $ 21.78万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444909
• 关键词: biological signal transduction; cytokine; cytokine receptors; gene mutation; interferon alpha; molecular cloning; protein tyrosine kinase; receptor binding; tissue /cell culture; transcription factor

DESCRIPTION: (Adapted from the investigator's abstract) Interferons (IFN), cytokines and growth factors play important roles as a first defense against viral infections, in the treatment of different types of cancers and in the regulation of the immune and hematopoietic system. Cytokines, growth factors and IFNs have similar signaling mechanisms that involve the activation of tyrosine kinases of the Jak family, and activation of transcription factors of the Stat family (Signal Transducers and Activators of Transcription), having as a final result the transcriptional activation of the genes responsible for the different cytokine responses. In the last three years, significant progress has been achieved in terms of knowing how the Stat factors activate gene transcription. However, little is known about the mechanisms by which cytokine receptors activate the Jak kinases and Stat factors. It has been proposed that the Stat factors are recruited to the IL-6 and IFN-gamma receptor complexes through the interaction of the Stat-SH2 domains with phosphotyrosine residues on the receptor subunits. However, this model is not compatible with those cytokine receptors such as the erythropoietin and growth hormone receptors in which tyrosine phosphorylation of receptor subunits is not required for signaling. Based on data obtained with the long form of the beta subunit of the IFN-alpha receptor (IFNaR), the applicant proposes an alternative model in which Stat factors constitutively interact with receptor subunits resulting in a constitutive Receptor-Jak-Stat complex. This proposal will test this model and will attempt to fill the gap of knowledge concerning how cytokine receptors activate the Jak kinases and the Stat transcription factor. Using the IFNaR as a working system, he will test the constitutive association of the Stat factors with IFNaR receptor subunits, and then determine if a similar model applies to other cytokine receptors. The results obtained with this proposal will be important for our long term objectives that involve the elucidation of the crosstalk between cytokine systems such the IFN system that have a negative regulatory effect on cell proliferation, and growth factors/cytokines that mediate cell proliferation.

描述：(改编自研究人员摘要)干扰素(干扰素)， 细胞因子和生长因子作为第一道防线发挥着重要作用。 病毒感染，在治疗不同类型的癌症和在 调节免疫和造血系统。细胞因子、生长 因子和IFN具有类似的信号机制，涉及 JAK家族酪氨酸激酶的激活，以及JAK家族的激活 STAT家族的转录因子(信号转导和激活因子 转录)，最终结果是转录激活 负责不同细胞因子反应的基因。 在过去三年中，在以下方面取得了重大进展 了解Stat因子如何激活基因转录。然而，几乎没有 已知细胞因子受体激活JAK的机制 蛋白水解酶和状态因子。有人提出，统计因素是 通过IL-6和干扰素-γ受体复合体被招募 Stat-SH2结构域与磷酸酪氨酸残基的相互作用 受体亚基。然而，该型号与那些型号不兼容 细胞因子受体，如促红细胞生成素和生长激素受体 其中受体亚基的酪氨酸磷酸化不是必需的 发信号。 基于用长形的β亚基获得的数据 关于干扰素-α受体(IFNaR)，申请人在 哪些STAT因子与受体亚单位结构性地相互作用 在构成的受体-Jak-Stat复合体中。这项提案将检验这一点 模型并将尝试填补关于细胞因子如何 受体激活Jak激酶和Stat转录因子。vbl.使用 IFNAR作为一种工作系统，他将测试构成关联的 STAT因子与IFNaR受体亚基结合，然后确定是否有 类似的模型也适用于其他细胞因子受体。所获得的结果 这项建议对我们的长期目标将是重要的， 涉及阐明细胞因子系统之间的串扰，如 对细胞增殖有负面调节作用的干扰素系统，以及 调节细胞增殖的生长因子/细胞因子。