Intestinal Cell Growth Control: Role of Tyrosine Kinases

描述（由申请人提供）：我们有兴趣了解正常肠细胞如何调节其生长，以及这种调节的丧失如何导致恶性转化。我们的研究重点是Src激酶参与调控的分子机制。我们确定RACK 1作为一种新的底物和结合伙伴的Src，和抑制剂的Src激酶和结肠细胞生长。RACK1通过在G1检查点抑制Src活性来调节细胞生长。我们假设RACK1调节生长的其他方面，部分通过其对Src的抑制作用。为了验证这一假设，我们将：目的1：进一步分析Src和RACK 1调节结肠细胞生长的机制。研究集中于它们通过戈伊/W、有丝分裂期间的Sam68功能和细胞粘附对细胞周期进程的影响。一个RACK1突变体，是有缺陷的抑制Src活性将被用来区分Src依赖性和独立的机制RACK1功能。目的2：评估Src和RACK 1在蛋白质翻译中的功能。研究重点是它们调节蛋白质合成中关键Src底物、效应子和结合伴侣的翻译活性的机制。目的3：分析RACK 1诱导结肠癌细胞凋亡和Src促进结肠癌细胞存活的机制。研究主要集中在它们对内源性和外源性凋亡途径以及Akt细胞存活途径的影响。致癌酪氨酸激酶的内源性抑制剂在细胞周期中的关键检查点、细胞粘附位点以及蛋白质翻译和凋亡期间起作用，将对细胞生长施加强有力的和普遍的控制。这些功能的开发可用于开发新的和更强大的和选择性的人类结肠癌的治疗策略。

DESCRIPTION (provided by applicant): We are interested in understanding how normal intestinal cells regulate their growth and how loss of that regulation results in malignant transformation. Our research focuses on molecular mechanisms by which the Src kinases contribute to the regulation. We identified RACK1 as a novel substrate and binding partner of Src, and an inhibitor of Src kinases and colonic cell growth. RACK1 regulates cell growth by suppressing Src activity at the G1 checkpoint. We hypothesize that RACK1 regulates other aspects of growth, in part via its inhibitory influence on Src. To test this hypothesis, we will: Aim 1: Further analyze mechanisms by which Src and RACK1 regulate growth of colon cells. Studies focus on their influence on cell cycle progression through Gy/W, Sam68 function during mitosis, and cell adhesion. A RACK1 mutant that is defective for suppressing Src activity will be used to distinguish Src-dependent and independent mechanisms of RACK1 function. Aim 2: Assess Src and RACK1 function in protein translation. Studies focus on mechanisms by which they regulate translational activities of key Src substrates, effectors and binding partners involved in protein synthesis. Aim 3: Analyze mechanisms by which RACK1 induces apoptosis, and Src promotes survival of colon cells. Studies focus on their influence on the intrinsic and extrinsic apoptotic pathways, and on the Akt cell survival pathway. Endogenous inhibitors of oncogenic tyrosine kinases that work at critical checkpoints in the cell cycle, at sites of cell adhesion and during protein translation and apoptosis, would exert powerful and pervasive control over cell growth. Exploitation of these multiple functions could be used to develop new and more powerful and selective strategies for treatment of human colon cancer.