CYCLIN D1 AND CDK4 INDUCE HYPERTROPHY THROUGH PHOSPHORYLATION OF RNA POLYMERASE II C-TERMINAL DOMAIN IN NEONATAL RAT CARDIOMYOCYTES

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We have previously reported that hypertrophic stimuli induce the expression of cyclinD1 and CDK4 in cardiomyocytes, and that overexpression of cyclin D1 and CDK4 causes hypertrophic change. Recently, it is reported that pTEFb (CDK9 and cyclinT) is involved in cardiac hypertrophy through phosphorylation of the RNA polymerase Ⅱ C-terminal domain (pol Ⅱ CTD), promoting transcript elongation by Pol Ⅱ. We assessed the hypothesis that cyclinD1/CDK4 induce hypertrophy through phosphorylation of pol Ⅱ CTD in cultured neonatal rat cardiomyocytes. In this study, we examined whether the overexpression of cyclinD1/CDK4 induces hypertrophy by using［3H］ leucine incorpolation assay. CyclinD1/CDK4 overexpression increased the rate of protein synthesis by 1.55 fold, compared to those in LacZ-overexpressed cells. Further, we assayed the rate of RNA synthesis by［3H］uridine incorpolation. Results showed that CyclinD1/CDK4 cells increased the rate of RNA synthesis compared to the control cells (1.57 fold).Finally, we examined whether phophorylation of pol Ⅱ CTD is involved in cyclinD1/CDK4-induced hypertrophy. DRB, a chemical antagonist of pol Ⅱ CTD phosphorylation, decreased the rate of incorporation of［3H］leucine and uridine in cyclinD1/CDK4 cells. These data altogether suggest that cyclinD1/CDK4 activates Pol Ⅱ transcription through inducing CTD phosphorylation and is involved in cardiac hypertrophy.