P27kip1 as an early effector of pRB function

描述：（改编自研究者摘要）肿瘤抑制因子 视网膜母细胞瘤蛋白在视网膜母细胞瘤中重新表达时抑制细胞增殖。 pRB缺陷型肿瘤细胞。我们的目标是找出 pRB功能的潜在机制。目前最受欢迎的模型 pRB与转录因子E2 F形成复合物 抑制某些基因的表达，这些基因的编码蛋白质促进细胞增殖， 增殖缺乏这些促进生长的蛋白质， 阻断DNA复制的起始。模型的后一方面 然而，仍有待实验测试。我们发现随着时间的推移 在pRB缺陷肿瘤中控制pRB再表达后的过程实验 细胞周期蛋白EfCdk 2和细胞周期蛋白A/Cdk 2的蛋白水平，也许是最重要的 pRB的重要抑制靶点，在GI细胞周期开始后下降 逮捕了然而，这些复合物的激酶活性被抑制， Gi期阻滞的发生是由早期增加的蛋白质水平， 细胞周期蛋白依赖性激酶抑制剂p27 Kipl。因此，我们假设p27是 pRB功能的早期效应子。在这个应用程序中，我们将实现两个 具体目的是检验这一假设。在目标1中，我们将确定 pRB介导的01停滞中的p27水平增加。我们的第二个目标是确定 pRB诱导细胞中p27水平的机制。虽然没有找到 由于p27在人类肿瘤中发生突变， 更具有侵袭性的肿瘤含有较低水平的p27， 降解成功完成拟议的研究不仅将 为pRB的功能机制提供了新的认识，同时也揭示了 p27参与癌症的新机制。更好地了解 连接细胞内各种负调节因子的复杂调节网络 扩散有很大的潜力揭示脆弱的步骤， 癌症治疗中的治疗靶向，我们的长期目标 research.

DESCRIPTION: (Adapted from the investigator's abstract) The tumor suppressor retinoblastoma protein inhibits cell proliferation when re-expressed in pRB-deficient tumor cells. Our objective is to identify the molecular mechanisms underlying this function of pRB. The currently most accepted model for pRB function is that pRB forms complexes with the transcription factor E2F to repress the expression of certain genes whose encoded proteins promote cell proliferation. The lack of these growth promoting proteins will then pose a block to the initiation of DNA replication. This latter aspect of the model however remains to be tested experimentally. We have discovered that, in time course experiments after controlled re-expression of pRB in pRB-deficient tumor cells, protein levels of cyclin EfCdk2 and cyclin A/Cdk2, perhaps the most important repression targets of pRB, declined after the onset of GI cell cycle arrest. The kinase activities of these complexes however were inhibited with the onset of Gi arrest by an early increase in the protein levels of the cyclin-dependent kinase inhibitor p27Kipl. We therefore hypothesize that p27 is an early effector of pRB function. In this application, we will achieve two specific aims to test this hypothesis. In aim 1, we will determine the role of p27 level increase in pRB-mediated 01 arrest. Our second aim is to determine the mechanisms by which pRB induces p27 levels in the cell. Although not found mutated in human tumors, p27 has been implicated in tumor prognosis by the fact that more aggressive tumors contain lower levels of p27 due to active protein degradation. Successful completion of the proposed studies will not only provide new knowledge about the functional mechanism of pRB but also reveal a new mechanism for the involvement of p27 in cancer. A better understanding of the complex regulatory networks linking various negative regulators of cell proliferation has the great potential of revealing vulnerable steps for therapeutic targeting in the treatment of cancer, a long-term objective of our research.