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域（RUNX）转录因子是动物发育的关键调节因子。三个哺乳动物Runx基因中的每一个都需要开发主要器官系统，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。 runxl是确定性造血所必需的，是人白血病中最常见的突变基因。 runx2是成骨所必需的，其单倍不使人间隙会导致裂解症状发育不全； Runx3是背根神经节神经发育和控制发育中胃中的细胞增殖所必需的，并且在人类胃癌中经常被删除或沉默。该赠款的目的是定义Runx蛋白在发育过程中控制细胞增殖的分子机制。为此，我们将海胆胚发生作为简化的模型系统。与具有3个Runx基因的哺乳动物不同，海胆purpuratus的海胆螺旋体仅具有一个Runx基因（Sprunt）。与其他RunX蛋白一样，Sprunt形成具有β亚基（SPCBFBETA）的异二聚体。我们的初步数据表明，胚胎发生过程中细胞增殖的正常程序和细胞周期蛋白D的转录激活是必需的。该赠款的具体目的是：（1）进一步定义弹簧在细胞增殖中的作用； （2）确定在循环顺式调节系统的上下文中弹力的功能； （3）调查其异二聚体伴侣Spcbfbeta在发育中的流动活动。这些目标将通过利用海胆胚胎的优势作为细胞生理学，基因调节和发育的生化和分子分析的系统，以及紫over链球菌基因组序列的可用性，这将在很大程度上促进基因的顺式调节性分析，并通过纯化的原始原料来识别纯化的原始原料素。