Abstract 299: Cell Division Cycle 7 Mediates Transforming Growth Factor-ß-induced Smooth Muscle Maturation

Abstract

Cell division cycle 7 (Cdc7) has been shown to regulate cell fate determination in the initial phase of transforming growth factor-β (TGF-β)-induced smooth muscle cell (SMC) differentiation. It is unknown, however, if Cdc7 is involved in SMC maturation or the late phase differentiation. In this study, we found that Cdc7 regulates the late phase SMC differentiation through a mechanism different from the cell fate determination. Knockdown of Cdc7 suppresses TGF-β-induced expression of smooth muscle myosin heavy chain (SMMHC), a late marker of SMC differentiation in addition to the early markers. Cdc7 overexpression, on the other hand, enhances SMMHC expression. Interestingly, Cdc7 activates the mRNA expression and gene transcription of myocardin (Myocd), a master regulator for SMC differentiation, whose transcription is blocked in the initial phase of the differentiation because TGF-β does not induce Myocd mRNA until 16 h after the stimulation. These data suggest that Cdc7 mediates TGF-β-induced late SMC differentiation via activating Myocd. Mechanistically, Cdc7 physically and functionally interacts with Nkx2.5 to regulate Myocd promoter activity. Cdc7 appears to enhance Nkx2.5 binding to Myocd promoter, leading to Myocd activation. Taken together, our studies demonstrate that Cdc7 regulates the initial and late phase of SMC differentiation through distinct mechanisms.