Multi step tumorigenesis, control of cell cycle entry

致癌作用是由多种协同遗传病变引起的，导致细胞信号传导和细胞周期限制点控制的进行性失调。所涉及的突变导致癌基因激活或肿瘤抑制基因功能丧失。然而，这些突变基因在恶性细胞转化中合作的机制在很大程度上是未知的。我们的实验室已经表明，致癌病变的合作涉及到多个信号的整合，集中在细胞周期依赖性激酶复合物的调节。在这里，我们建议调查的c-myc癌基因与激活Ras/Raf信号合作的分子机制。c-myc癌基因在人类癌症中经常被激活，并且是增殖和凋亡的有效诱导剂。Myc诱导的增殖中的一个重要步骤是细胞周期蛋白E依赖性激酶（Cyclin E/Cdk 2）的激活。利用组织培养中的遗传和生物化学方法，我们最近做出了令人惊讶的发现，c-myc激活细胞周期蛋白E/Cdk 2需要D细胞周期蛋白的能力，以隔离G1期细胞周期抑制剂p27 Kip 1和p21 Cip 1（Ckis）。我们现在建议调查是否有能力的D细胞周期蛋白螯合CKIS起着重要的作用，在一个完整的生物体中激活的c-myc诱导细胞分裂。此外，我们计划茶的假设，螯合CKIS的D细胞周期蛋白可能发挥重要作用，在器官发育和多步骤癌变。这项工作将为开发基于信号通路的人类癌症治疗策略提供见解。

Carcinogenesis is caused by multiple co-operating genetic lesions leading to a progressive deregulation of cellular signaling and cell cycle restriction point control. The mutations involved result in oncogene activation or loss of tumor-suppressor gene function. However, the mechanisms by which these mutant genes co-operate in malignant cell transformation are largely unknown. Our laboratory has shown that the co-operation of oncogenic lesions involves integration of multiple signals converging on the regulation of cell cycle-dependent kinase complexes. Here we propose to investigate the molecular mechanisms by which the c-myc oncogene co-operates with activated Ras/Raf signaling. The c-myc oncogene is frequently activated in human cancer and is a potent inducer of proliferation and apoptosis. One essential step in Myc-induced proliferation is the activation of Cyclin E-dependent kinase (Cyclin E/Cdk2). Using genetic and biochemical approaches in tissue culture, we recently made the surprising finding that activation of cyclin E/Cdk2 by c-myc requires the ability of D cyclins to sequester Gl cell cycle inhibitors p27Kip1 and p21Cip1 (Ckis). We now propose to investigate whether the capability of D cyclins to sequester Ckis plays an important role in the induction of cell division by activated c-myc in an intact organism. Moreover, we plan to tea the hypothesis that sequestration of Ckis by D cyclins may play a significant role in organ development and during multi-step carcinogenesis. This work will provide insight into developing signaling pathway-based strategies for cancer therapy in humans.