GENISTEIN INDUCES P21(CIP1 WAF1) EXPRESSION AND BLOCKS THE G1 TO S-PHASE TRANSITION IN MOUSE FIBROBLAST AND MELANOMA-CELLS/

Genistein, the principal isoflavonoid in soybeans, is reported to inhi bit cell cycle progression but the molecular basis for this event is u nknown. Here we show that genistein inhibits DNA synthesis and suppres ses cyclin E-associated cyclin-dependent kinase-2 (CDK2) activity when quiescent BALB/c 3T3 fibroblasts are stimulated with serum. In these cells, a CDK2 inhibitor, p21(Cip1/WAF1), is markedly increased by geni stein, but another CDK2 inhibitor, p27(Kip1), is not increased. In exp onentially growing BALB/c 3T3 cells, genistein inhibits proliferation of the cells in a dose-dependent manner. Flow cytometric analysis and measurement of DNA synthesis indicate that genistein blocks the G1 to S phase transition of these cells, which is concomitant with G2-M arre st. In mouse B16-F1 melanoma cells, genistein also blocks the transiti on of G1 to S phase without arresting at G2-M at low doses. In both ce ll lines, genistein suppresses cyclin E/CDK2 activity and induces p21( Cip1/WAF1) expression. These results suggest that genistein affects th e restriction point control of the cell cycle by inducing p21(Cip1/WAF 1) expression in mouse fibroblast and melanoma cells. (C) 1998 Academi c Press.