INTESTINAL CELL GROWTH CONTROL: ROLE OF TYROSINE KINASES

描述（改编自申请人的摘要）：结肠癌是第三大癌症。 是美国癌症死亡的主要原因。本研究着重于 Src酪氨酸激酶在结肠癌发生中的作用。他人和 PI已经表明，Src活性的下调对于 分化和Src活性的上调是重要的 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， 在结肠癌中上调Src。假设是Src的特定结构域， 以及与之结合的蛋白质是Src活性的重要调节剂。 因此，致力于鉴定调节蛋白质的细胞蛋白质。 Src在肠细胞成熟和恶性转化中的作用。 利用酵母双杂交试验，PI最近确定了RACK 1，一种受体 对于活化的C激酶和G蛋白的β亚基的同系物， 新Src SH 2结合蛋白。PI发现RACK 1抑制了特定的 Src的活性和NIH 3 T3细胞的生长。RACK 1发挥其作用， 细胞生长，部分是通过延长细胞周期的G 0/G1期。的PI 将进一步描述Src的伙伴RACK 1和RACK 1的机制， 其功能是调节Src活性和肠细胞生长。一个目的是 评估两种蛋白质结合和磷酸化的需要 RACK 1，通过Src对RACK 1抑制Src活性和细胞生长。第二 目的是分析串扰发生的机制， RACK1-linked signaling pathways of Src and PKC.第三个目标是评估 RACK 1对v-Src细胞转化的影响。第四个目标是进一步 分析RACK 1对细胞周期和Src活性的影响， 细胞周期这些研究应该产生重要的新信息， 一种新型Src和细胞生长抑制剂。了解抑制剂是如何 促有丝分裂信号调节肠细胞生长， 抑制导致不受控制的生长和恶性转化，应 影响我们对结肠癌生物学的基本理解， 结肠癌治疗的新策略。内源性致癌抑制剂 激酶是潜在的肿瘤抑制剂;它们代表了令人兴奋的新靶点 进行治疗干预。

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.