SUPPRESSION OF CYCLIN D1 BUT NOT CDK4 OR CYCLIN-A WITH INDUCTION OF MELANOMA TERMINAL DIFFERENTIATION

To identify cyclins specifically associated with control of melanoma c ell proliferation, we now compared expression of cyclin A, reported to be a marker for hematological malignancies, with. that of cyclin D an d its cdk4 kinase partner. All these proteins were expressed in prolif erating B16 melanoma. However, L-tyrosine which induces melanoma termi nal differentiation, selectively decreased cyclin D with no comparable effect on cdk4 or cyclin A. A 5-hour exposure of the cells to the tyr osine phosphatase inhibitor, sodium vanadate,further decreased cyclin D from differentiated cells, suggesting that tyrosine phosphorylation regulates cyclin D turnover. Addition of serum to starved cells also r evealed that tyrosine did not block the early cyclin D increase associ ated with serum stimulation, but accelerated its subsequent loss. Our data suggest that cyclin D decrease with melanoma terminal differentia tion could be an alternative mode of growth arrest even in cells harbo uring a mutant or transcriptionally silent cdk4 inhibitor tumor suppre ssor p16(ink4) gene. These results also imply that cyclin D may be use ful as a target and as a prognostic marker in melanoma therapy. (C) 19 95 Academic Press, Inc.