Hematopoietic Cell Survival by Protein Kinase CISK

蛋白激酶 CISK 影响造血细胞存活

• 批准号: 7173149
• 负责人: Zhou Songyang
• 金额: $ 11.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173149
• 关键词: apoptosis; biological signal transduction; cell differentiation; cell proliferation; cytokine; cytotoxicity; genetic screening; genetically modified animals; hematopoietic stem cells; insulinlike growth factor; interleukin 3; laboratory mouse; peptide library; phosphatidylinositol 3 kinase; phospholipids; protein kinase; serine threonine protein kinase

DESCRIPTION (provided by applicant): Normal development of multi-cellular organisms relies on the balance between cell proliferation, differentiation and programmed cell death (PCD or apoptosis). Many types of human diseases including cancer appear to be associated with aberrant regulation of PCD and proliferation. Despite the wealth of information, mammalian-signaling pathways for survival and anti-PCD remain poorly understood. Survival and growth of hematopoietic cells as well as hematopoietic development depend on cytokines such as IL-3. We have been studying cell survival pathways using IL-3 signaling as a model system. Through a newly developed genetic screen, we have identified a number of novel factors as new components in survival signaling cascades. One of them is the Phox-homology (PX) domain containing serine/threonine kinase CISK (Cytokine-lndependent Survival Kinase). CISK is a new member of the SGK family kinases (SGK3), and the first to be shown capable of supporting cell survival. Our studies suggest that CISK may function downstream of PI-3 kinase and regulate Flightless homologue and GCF2 activities. The unique domain structure, tissue expression pattern, and subcellular localization of CISK also suggest that CISK plays a distinct role from Akt and other SGK family kinases. The overall objective of this proposal is to understand CISK signaling networks and to define the function of CISK in anti-apoptosis and development. The specific aims of this proposal are to: 1. Elucidate the signaling pathways modulated by CISK in vivo, by investigating the survival activity of endogenous CISK and its regulation of FLII and GCF2 function and activities. 2. Determine the biochemical mechanisms that control CISK activation and subcellular localization, by examining the regulation of its activities by cytokines and the unique domains of CISK. 3. Investigate the physiological role of CISK in cell survival and development in mice, by studying how CISK affects hematopoietic cell development and survival using chimeric and knock-out mouse models.

描述（由申请人提供）：多细胞生物体的正常发育依赖于细胞增殖、分化和程序性细胞死亡（PCD或凋亡）之间的平衡。包括癌症在内的许多类型的人类疾病似乎与PCD和增殖的异常调节有关。尽管有丰富的信息，但对生存和抗PCD的信号通路仍然知之甚少。造血细胞的存活和生长以及造血发育依赖于细胞因子如IL-3。我们一直在使用IL-3信号作为模型系统来研究细胞存活途径。通过一个新开发的遗传筛选，我们已经确定了一些新的因素作为生存信号级联的新组件。其中之一是含有丝氨酸/苏氨酸激酶CISK（细胞因子依赖性生存激酶）的Phox同源（PX）结构域。CISK是SGK家族激酶（SGK 3）的新成员，也是第一个被证明能够支持细胞存活的成员。我们的研究表明，CISK可能在PI-3激酶下游发挥作用，并调节Flightless同源物和GCF 2的活性。CISK独特的结构域结构、组织表达模式和亚细胞定位也表明，CISK发挥着与Akt和其他SGK家族激酶不同的作用。该提案的总体目标是了解CISK信号网络，并定义CISK在抗凋亡和发育中的功能。 这项建议的具体目标是：1.通过研究内源性CISK的存活活性及其对FLII和GCF 2功能和活性的调节，阐明CISK在体内调节的信号通路。2.通过检查细胞因子和CISK独特结构域对其活性的调节，确定控制CISK激活和亚细胞定位的生化机制。3.通过使用嵌合和敲除小鼠模型研究CISK如何影响造血细胞发育和存活，研究CISK在小鼠细胞存活和发育中的生理作用。