title: The positive transcription elongation factor b is an essential cofactor for the activation of transcription by myocyte enhancer factor 2.
abstract: The positive transcription elongation factor b (P-TEFb), composed of cyclin-dependent kinase 9 and cyclin T1, stimulates the elongation of transcription by hyperphosphorylating the C-terminal region of RNA polymerase II. Aberrant activation of P-TEFb results in manifestations of cardiac hypertrophy in mice, suggesting that P-TEFb is an essential factor for cardiac myocyte function and development. Here, we present evidence that P-TEFb selectively activates transcription mediated by the myocyte enhancer factor 2 (MEF2) family of transcription factors, key regulatory factors for myocyte development. Knockdown of endogenous cyclin T1 in murine C2C12 cells abolishes MEF2-dependent reporter gene expression as well as transcription of endogenous MEF2 target genes, whereas overexpression of P-TEFb enhances MEF2-dependent transcription. P-TEFb interacts with MEF2 both in vitro and in vivo. Activation of MEF2-dependent transcription induced by serum starvation is mediated by a rapid dissociation of P-TEFb from its inhibitory subunit, HEXIM1, and a subsequent recruitment of P-TEFb to MEF2 binding sites in the promoter region of MEF2 target genes. These results indicate that recruitment of P-TEFb is a critical step for stimulation of MEF2-dependent transcription, therefore providing a fundamentally important regulatory mechanism underlying the transcriptional program in muscle cells.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Yehong
authors.initials: Y
authors.lastname: Huang
authors.forename: Mudit
authors.initials: M
authors.lastname: Tyagi
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
authors.forename: Koh
authors.initials: K
authors.lastname: Fujinaga
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; C118642:Hexim1 protein, mouse; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011987:Receptors, Steroid; D014157:Transcription Factors; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases