title: Activation of MyoD-dependent transcription by cdk9/cyclin T2.
abstract: Myogenic transcription is repressed in myoblasts by serum-activated cyclin-dependent kinases, such as cdk2 and cdk4. Serum withdrawal promotes muscle-specific gene expression at least in part by down-regulating the activity of these cdks. Unlike the other cdks, cdk9 is not serum- or cell cycle-regulated and is instead involved in the regulation of transcriptional elongation by phosphorylating the carboxyl-terminal domain (CTD) of RNA polymerase II. While ectopic expression of cdk2 together with its regulatory subunits (cyclins E and A) inhibits myogenic transcription, overproduction of cdk9 and its associated cyclin (cyclin T2a) strengthens MyoD-dependent transcription and stimulates myogenic differentiation in both MyoD-converted fibroblasts and C2C12 muscle cells. Conversely, inhibition of cdk9 activity by a dominant negative form (cdk9-dn) represses the myogenic program. Cdk9, cyclinT2 and MyoD can be detected in a multimeric complex in C2C12 cells, with the minimal cdk9-binding region of MyoD mapping within 101-161 aa of the bHLH region. Finally, cdk9 can phosphorylate MyoD in vitro, suggesting the possibility that cdk9/cycT2a regulation of muscle differentiation includes the direct enzymatic activity of the kinase on MyoD.
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania, PA 19122, USA.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
authors.forename: Peter
authors.initials: P
authors.lastname: Stiegler
authors.forename: Luigi
authors.initials: L
authors.lastname: Bagella
authors.forename: Bruna
authors.initials: B
authors.lastname: Pucci
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bellan
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.forename: Antonio
authors.initials: A
authors.lastname: De Luca
authors.forename: Ginevra
authors.initials: G
authors.lastname: Guanti
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016213:Cyclins / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D051379:Mice; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein / Q000502:physiology*; D010766:Phosphorylation; D011233:Precipitin Tests; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C441622:CCNT2 protein, human; D056906:Cyclin T; D016213:Cyclins; D017570:MyoD Protein; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases