INTESTINAL CELL GROWTH CONTROL: ROLE OF TYROSINE KINASES

肠细胞生长控制：酪氨酸激酶的作用

• 批准号: 6634979
• 负责人: CHRISTINE Ann CARTWRIGHT
• 金额: $ 24.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634979
• 关键词: athymic mouse; binding proteins; cell cycle; cell growth regulation; chimeric proteins; colon neoplasms; enzyme activity; enzyme mechanism; genetic library; growth inhibitors; intestines; neoplasm /cancer genetics; neoplastic transformation; protein kinase C; protein tyrosine kinase; protooncogene; tissue /cell culture; western blottings; yeast two hybrid system

DESCRIPTION (Adapted from the Applicant's Abstract): Colon cancer is the third leading cause of cancer deaths in the United States. This research focuses on the role of the Src tyrosine kinase in colonic carcinogenesis. Others and the PI have shown that downregulation of Src activity is important for differentiation and that upregulation of Src activity is important for malignant transformation of intestinal cells. Thus, the goal is to define molecular mechanisms that downregulate Src in normal colon and those that upregulate Src in colon cancer. The hypothesis is that specific domains of Src, and the proteins that bind to them, are important regulators of Src activity. Thus, effort is directed towards identifying cellular proteins that modulate Src function during intestinal cell maturation and malignant transformation. Using a yeast two-hybrid assay, the PI recently identified RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, as a novel Src SH2-binding protein. The PI found that RACK1 inhibits the specific activity of Src and the growth of NIH 3T3 cells. RACK1 exerts its effect on cell growth, in part, by prolonging the G0/G1 phase of the cell cycle. The PI will further characterize Src's partner RACK1 and the mechanism by which RACK1 functions to regulate Src activity and intestinal cell growth. One aim is to assess the requirement of binding of the two proteins and of phosphorylation of RACK1, by Src for RACK1 inhibition of Src activity and cell growth. The second aim is to analyze the mechanism by which cross talk occurs between the RACK1-linked signaling pathways of Src and PKC. The third aim is to assess RACKl's influence on cell transformation by v-Src. The fourth aim is to further analyze the effect of RACK1 on the cell cycle and on Src activity during the cell cycle. These studies should generate significant new information regarding a novel inhibitor of Src and cell growth. Understanding how inhibitors of mitogenic signals work to regulate intestinal cell growth and how loss of that inhibition results in uncontrolled growth and malignant transformation, should impact our basic understanding colon cancer biology and lead to development of novel strategies for colon cancer therapy. Endogenous inhibitors of oncogenic kinases are potentially tumor suppressors; they represent exciting new targets for therapeutic intervention.

描述（改编自申请人的摘要）：结肠癌是第三个 美国癌症死亡的主要原因。这项研究重点 SRC酪氨酸激酶在结肠致癌作用中的作用。其他和 PI表明SRC活性的下调对于 分化和SRC活动的上调对于 肠细胞的恶性转化。因此，目标是定义 在正常结肠中下调SRC的分子机制和 在结肠癌中上调SRC。假设是SRC的特定域 与它们结合的蛋白质是SRC活性的重要调节剂。 因此，努力用于识别调节的细胞蛋白 肠细胞成熟和恶性转化过程中的SRC功能。 使用酵母两杂交测定法，PI最近确定了RACK1，一种受体 用于激活的C激酶和G蛋白的β亚基的同源物作为A 新型SRC SH2结合蛋白。 PI发现RACK1抑制了特定 SRC的活性和NIH 3T3细胞的生长。架子1对 细胞生长部分通过延长细胞周期的G0/G1相。 pi 将进一步描述SRC的合作伙伴Rack1和Rack1的机制 调节SRC活性和肠细胞生长的功能。一个目的是 评估两种蛋白质结合和磷酸化的要求 RACK1，由SRC进行RACK1抑制SRC活性和细胞生长。第二个 目的是分析交叉谈话之间发生的机制 SRC和PKC的RACK1连接信号通路。第三个目的是评估 RACKL对V-SRC对细胞转换的影响。第四个目标是进一步 分析RACK1对细胞周期和SRC活性的影响 细胞周期。这些研究应产生有关的重要新信息 SRC和细胞生长的新型抑制剂。了解如何抑制剂 有丝分裂信号可调节肠细胞生长以及该损失 抑制作用导致不受控制的生长和恶性转化，应 影响我们的基本了解结肠癌生物学，并导致发展 结肠癌疗法的新型策略。内源性抑制剂 激酶是潜在的肿瘤抑制剂。它们代表令人兴奋的新目标 用于治疗干预。