P53-INDEPENDENT INCREASE IN P21WAF1 AND RECIPROCAL DOWN-REGULATION OFCYCLIN-A AND PROLIFERATING CELL NUCLEAR ANTIGEN IN BROMODEOXYURIDINE-MEDIATED GROWTH ARREST OF HUMAN-MELANOMA CELLS

Differentially regulated expression of activators and inhibitors of cy clin-dependent kinases (cdks) modulate cell cycle progression, In norm al fibroblasts, these complexes consist of the cdk inhibitor p21WAF1/P CNA/G1 cyclin/cdk. We now show that bromodeoxyuridine (BrdUrd), a thym idine analogue and radiation sensitizer, inhibits growth and activity of cyclin A-cdk2 kinase in metastatic C8161 and nonmetastatic neo 6.3/ C8161 human melanoma cells. Inhibition is not due to altered levels of cyclin D or catalytic cdk2 but involves a decrease in cyclin A and pr oliferating cell nuclear antigen, paralleled by higher levels of p21WA F1 without increases in p53, In contrast to serum starvation, which pr events accumulation of cyclins A and D in normal fibroblasts, such tre atment did not down-regulate either cyclin in these melanoma cells, im plying an aberrant control for G1 cyclins in these tumor cells, Howeve r, cyclin A was decreased by BrdUrd, suggesting that this pyrimidine a nalogue arrests melanoma cells at a G1 transition point, unlike that o f serum starvation, This is the first report indicating that the antit umor therapeutic action of BrdUrd may be mediated by a p53-independent reciprocal effect on activators and inhibitors of cdk kinases.