title: Cell division cycle 7 mediates transforming growth factor-β-induced smooth muscle maturation through activation of myocardin gene transcription.
abstract: Smooth muscle (SM) development consists of several processes, including cell fate determination, differentiation, and maturation. The molecular mechanisms controlling SM early differentiation have been studied extensively. However, little is known about the mechanism underlying SM maturation. 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 SM differentiation. Our present study indicates that Cdc7 also regulates SM maturation. Knockdown of Cdc7 suppresses TGF-β-induced expression of SM myosin heavy chain, a late marker of SM differentiation. Cdc7 overexpression, on the other hand, enhances SM myosin heavy chain expression. Interestingly, Cdc7 activates the mRNA expression and promoter activity of myocardin (Myocd), a master regulator of SM differentiation, whose transcription is blocked in the initial phase of the differentiation because TGF-β does not induce Myocd mRNA until after the early SM markers are induced. These data suggest that Cdc7 mediates TGF-β-induced SM maturation via activation of Myocd transcription. 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 SM differentiation through distinct mechanisms.
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia 30602.
authors.forename: Ning
authors.initials: N
authors.lastname: Shi
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D051379:Mice; D009130:Muscle, Smooth / Q000254:growth & development* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099251:Myocardin; C489403:Cdc7 protein, mouse
keywords: Cell Division Cycle 7; Differentiation; Gene Regulation; Gene Transcription; Smooth Muscle; Smooth Muscle Maturation; Transforming Growth Factor-β (TGF-β)