MYC INDUCES CYCLIN D1 EXPRESSION IN THE ABSENCE OF DE-NOVO PROTEIN-SYNTHESIS AND LINKS MITOGEN-STIMULATED SIGNAL-TRANSDUCTION TO THE CELL-CYCLE

Mitogen-activated signal transduction frequently leads to the inductio n of the c-myc proto-oncogene, but the subsequent molecular events dow nstream of Myc protein expression which promote cell cycle progression remain unclear. To study Myc-specific effects, without the complexity of the broader proliferative response evoked by serum, we employed th e MycER-inducible system in the non-transformed Rat-1 cell line. We de monstrate that activation of wild-type, but not mutant, MycER is suffi cient to transiently induce cyclin D1 RNA as well as protein expressio n to physiological levels, and promote G0/G1 to S phase transition of the cell cycle. Stimulation of endogenous cyclin D1 RNA is rapid and c learly evident within 30 min of MycER-activation, reaching a peak at 3 h. Nuclear run-on analysis demonstrates that this induction occurs at the transcriptional level with a fivefold increase in the rate of tra nscription. Moreover, MycER induces cyclin D1 transcription with equal efficacy in the presence or absence of de novo protein synthesis. Our work shows that Myc and cyclin D1 lie consecutively in a major prolif eration-control pathway, and together create a pivotal connection betw een signal transduction and cell cycle control.