Cell Cycle Start Control

我们在理解贴壁依赖性和非贴壁依赖性细胞周期启动机制方面取得了相当大的进展，这是恶性转化细胞使肿瘤形成和转移的能力的基础。以下是主要调查结果。1.当锚定丧失时，染色体复制的起始物Cdc 6的表达通过启动子关闭和促进蛋白水解而终止。2.两种泛素连接酶和一种组织蛋白酶样半胱氨酸蛋白酶负责这种蛋白水解。3.其中一种连接酶是已知在G1中降解Cdc 6的Cdhl-APC，但我们发现其功能需要p53隐性癌蛋白。4.这些系统对Cdc 6的降解似乎受到与PI 3 K和mTOR连接的Tsc-Rheb介导的信号的调节。此外，我们已经发现，细胞周期蛋白Ds和它们的伴侣激酶Cdk 6/D3的特定组合逃避抑制剂蛋白的抑制，因此具有在生长抑制条件下促进细胞增殖的独特能力，并且似乎因此增强细胞对化学诱导的恶性转化的易感性。我们在理解通过酪氨酸磷酸化调节细胞周期蛋白依赖性激酶的分子机制方面取得了进展，并发现了Cdc 25 A中磷酸化非依赖性DDG基序的存在，其被TrCP-SCFb识别，已知TrCP-SCFb仅在磷酸化后识别这种基序。

We have made considerable progress in understanding the mechanism of anchorage-dependent and independent cell cycle onset, the basis for the ability of malignantly transformed cells to make tumor formation and metastasis. The following is the key findings made. 1. Upon anchorage loss, expression of Cdc6 the initiator of chromosomal replication is terminated by both promoter shutdown and by facilitated proteolysis. 2. Two ubiquitin ligases and one cathepsins-like cysteine protease are responsible for this proteolysis. 3. One of the ligases is Cdhl-APC known to degrade Cdc6 in Gl, but we found requires p53 recessive oncoprotein for its function. 4. The degradation of Cdc6 by these systems appears to be regulated by signals mediated by Tsc-Rheb linked to PI3K and mTOR. In addition, we have found that a particular combination of cyclin Ds and their partner kinases, Cdk6/D3 evades inhibitions by inhibitor proteins and consequently has a unique ability to promote cell proliferation under growth suppressive conditions, and seemingly therefore enhance susceptibility of cells to chemically induced malignant transformation.On the other hands, we have made progress in understanding the molecular mechanism involved in the regulation of cyclin-dependent kinases by tyrosine phosphorylation and discovered the occurrence of the phosphorylation-independent DDG motif in Cdc25A, which is recognized by TrCP-SCFb that is known to recognize such a motif only after being phosphorylated.