Activation of MyoD-dependent transcription by cdk9/cyclin T2.
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.
Simone
Cristiano
C
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania, PA 19122, USA.
Stiegler
Peter
P
Bagella
Luigi
L
Pucci
Bruna
B
Bellan
Cristiana
C
De Falco
Giulia
G
De Luca
Antonio
A
Guanti
Ginevra
G
Puri
Pier Lorenzo
PL
Giordano
Antonio
A
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*
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