Control of Cell Proliferation by Runx Proteins

Runx 蛋白对细胞增殖的控制

• 批准号: 7106846
• 负责人: JAMES A COFFMAN
• 金额: $ 14.46万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106846
• 关键词: Control; Cell; Proliferation; Runx; Proteins

DESCRIPTION (provided by applicant): Runt domain (Runx) transcription factors are key regulators of animal development. Each of the three mammalian Runx genes is required for the development of a major organ system, and in humans all three are associated with disease caused by uncontrolled cell proliferation. RUNXl is required for definitive hematopoiesis, and is the most frequently mutated gene in human leukemia; RUNX2 is required for osteogenesis, and its haploinsufficiency causes cleidocranial dysplasia; and RUNX3 is required for neural development in the dorsal root ganglia and for control of cell proliferation in the developing stomach, and is frequently deleted or silenced in human stomach cancer. The purpose of this grant is to define the molecular mechanisms through which Runx proteins control cell proliferation during development. Toward this end we are using sea urchin embryogenesis as a simplified model system. Unlike mammals, which have 3 Runx genes, the sea urchin Strongylocentrotus purpuratus has only a single Runx gene (SpRunt). As is the case with other Runx proteins, SpRunt forms a heterodimer with a beta subunit (SpCBFbeta). Our preliminary data show that SpRunt is required for the normal program of cell proliferation during embryogenesis and for the transcriptional activation of cyclin D. The specific aims of this grant are: (1) to further define the roles of SpRunt in cell proliferation; (2) to determine how SpRunt functions within the context of the cyclinD cis-regulatory system; and (3) to investigate how SpRunt activity is developmentally regulated by its heterodimeric partner, SpCBFbeta. These aims will be achieved by exploiting the strengths of the sea urchin embryo as a system for biochemical and molecular analyses of cell physiology, gene regulation, and development, and the availability of the S. purpuratus genome sequence, which will greatly facilitate both the cis-regulatory analysis of genes and the identification of purified proteins by mass spectrometry.

描述（由申请人提供）： Runt结构域（Runx）转录因子是动物发育的关键调控因子。哺乳动物的三个Runx基因中的每一个都是主要器官系统发育所必需的，在人类中，这三个基因都与不受控制的细胞增殖引起的疾病有关。RUNX 1是确定性造血所需的，并且是人白血病中最频繁突变的基因; RUNX 2是骨生成所需的，并且其单倍性不足引起锁骨颅骨发育不良; RUNX 3是背根神经节中的神经发育和发育中的胃中的细胞增殖的控制所需的，并且在人胃癌中经常缺失或沉默。这项资助的目的是确定Runx蛋白在发育过程中控制细胞增殖的分子机制。为此，我们使用海胆胚胎发生作为简化的模型系统。与哺乳动物有3个Runx基因不同，海胆只有一个Runx基因（SpRunt）。与其他Runx蛋白一样，SpRunt与β亚基（SpCBFbeta）形成异二聚体。我们的初步数据表明，SpRunt是胚胎发生过程中细胞增殖的正常程序和细胞周期蛋白D的转录激活所必需的。这项资助的具体目的是：（1）进一步确定SpRunt在细胞增殖中的作用;（2）确定SpRunt如何在cyclinD顺式调节系统中发挥作用;（3）研究SpRunt活性如何通过其异源二聚体伴侣SpCBFbeta进行发育调节。这些目标将通过利用海胆胚胎作为细胞生理学、基因调控和发育的生化和分子分析系统的优势以及S.这将极大地促进基因的顺式调控分析和通过质谱法鉴定纯化的蛋白质。