Accumulation of high levels of the p53 and p130 growth-suppressing proteins in cell lines stably over-expressing cyclin-dependent kinase 6 (cdk6)

Cyclin-dependent kinase 6(cdk6) is present in randomly proliferating cultures of 3T3 cells but has little detectable enzymatic activity, Significant activity is detected only during a short period in early G1 phase. To examine the possible functions of cdk6 in 3T3 cells, lines stably over-expressing cdk6 were constructed and compared to normal 3T3 cells or cell lines with reduced cdk6 levels due to expression of a dominant-negative form of the protein, Over-expression of cdk6 in cells, which led to high levels of activity even in proliferating cultures, had dramatic effects, Cell lines stably over-expressing wild-type cdk6 had a markedly reduced growth rate compared to parental 3T3 cells or lines expressing a dominant-negative form of cdk6. They also over-produced the p53 and p130 proteins and had increased sensitivity to UV-irradiation. Irradiation resulted in accumulation of the Bas protein and rapid cell death, Levels of p53 and p130 proteins were downregulated and the growth rate of the cells was increased by introduction of the dominant-negative form of cdk6 into cells over-expressing cdk6, indicating that cdk6 is involved in the overproduction of p53 and p130. The results suggest that cdk6, through regulation of growth suppressing molecules, may play a role in halting cellular growth when proliferation is inappropriate. Oncogene, (2001) 20, 2889-2899.