Cell Cycle Start Control

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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.