Cell Growth & Differentiation, Vol 7, Issue 2 197-202, Copyright © 1996 by American Association of Cancer Research

ARTICLES

p53-independent increase in p21WAF1 and reciprocal down-regulation of cyclin A and proliferating cell nuclear antigen in bromodeoxyuridine-mediated growth arrest of human melanoma cells

M Strasberg Rieber, DR Welch, ME Miele and M Rieber
IVIC, Tumor Cell Biology, Caracas, Venezuela. mrieber/pasteur.ivic.ve

Differentially regulated expression of activators and inhibitors of cyclin-dependent kinases (cdks) modulate cell cycle progression. In normal fibroblasts, these complexes consist of the cdk inhibitor p21WAF1/PCNA/G1 cyclin/cdk. We now show that bromodeoxyuridine (BrdUrd), a thymidine 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 proliferating cell nuclear antigen, paralleled by higher levels of p21WAF1 without increases in p53. In contrast to serum starvation, which prevents accumulation of cyclins A and D in normal fibroblasts, such treatment did not down-regulate either cyclin in these melanoma cells, implying an aberrant control for G1 cyclins in these tumor cells. However, cyclin A was decreased by BrdUrd, suggesting that this pyrimidine analogue arrests melanoma cells at a G1 transition point, unlike that of serum starvation. This is the first report indicating that the antitumor therapeutic action of BrdUrd may be mediated by a p53-independent reciprocal effect on activators and inhibitors of cdk kinases.

This article has been cited by other articles:

				C. Schorl and J. M. Sedivy Loss of Protooncogene c-Myc Function Impedes G1 Phase Progression Both before and after the Restriction Point Mol. Biol. Cell, March 1, 2003; 14(3): 823 - 835. [Abstract] [Full Text] [PDF]

				L. Solorzano, M. S. Rieber, and M. Rieber Lower Cyclin H and Cyclin-dependent Kinase-activating Kinase Activity in Cell Cycle Arrest Induced by Lack of Adhesion to Substratum Cancer Res., December 1, 2000; 60(24): 7114 - 7118. [Abstract] [Full Text]