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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bagella L, MacLachlan TK, Buono RJ, Pisano MM, Giordano A, De Luca A . 1998 J. Cell. Physiol. 177: 206–213
Bagella L, Stiegler P, De Luca A, Siracusa LD, Giordano A . 2000 J. Cell. Biochem. 78: 170–178
Dahmus ME . 1996 J. Biol. Chem. 271: 19009–19012
De Falco G, Giordano A . 1998 J. Cell. Physiol. 177: 501–506
De Falco G, Bagella L, Claudio PP, De Luca A, Fu Y, Calabretta B, Sala A, Giordano A . 2000 Oncogene 19: 373–379
De Luca A, MacLachlan TK, Bagella L, Dean C, Howard CM, Claudio PP, Baldi A, Khalili K, Giordano A . 1997a J. Biol. Chem. 272: 20971–20974
De Luca A, Esposito V, Baldi A, Claudio PP, Fu Y, Caputi M, Pisano M, Baldi F, Giordano A . 1997b J. Cell. Physiol. 172: 265–273
Eckner R, Yao TP, Oldread E, Livingston DM . 1996 Genes Dev. 10: 2478–2490
Edwards MC, Wong C, Elledge SJ . 1998 Mol. Cell. Biol. 18: 4291–4300
Foskett SM, Ghose R, Tang DN, Lewis DE, Rice AP . 2001 J. Virol. 75: 1220–1228
Fu TJ, Peng J, Price DH, Flores O . 1999 J. Biol. Chem. 274: 34527–34530
Garriga J, Peng J, Parreno M, Price DH, Henderson EE, Grana X . 1998 Oncogene 17: 3093–3102
Grana X, De Luca A, Sang N, Fu Y, Claudio PP, Rosenblatt J, Morgan DO, Giordano A . 1994 Proc. Natl. Acad. Sci. 91: 3834–3838
Gu W, Schneider JW, Condorelli G, Kaushal S, Mahdavi V, Nadal-Ginard B . 1993 Cell 72: 309–324
Guo K, Walsh K . 1997 J. Biol. Chem. 272: 791–797
Herrmann CH, Carroll RG, Wei P, Jones KA, Rice AP . 1998 J. Virol. 72: 9881–9888
Kanazawa S, Okamoto T, Peterlin BM . 2000 Immunity 12: 61–70
Kitzmann M, Vandromme M, Schaeffer V, Carnac G, Labbe JC, Lamb N, Fernandez A . 1999 Mol. Cell. Biol. 19: 3167–3176
Kwak YT, Ivanov D, Guo J, Nee E, Gaynor RB . 1999 J. Mol. Biol. 288: 57–69
Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H . 1991 Cell 66: 305–315
Lassar A, Münsterberg A . 1994 Curr. Opin. Cell Biol. 6: 432–442
Lis JT, Mason P, Peng J, Price DH, Werner J . 2000 Genes Dev. 14: 792–803
MacLachlan TK, Sang N, Giordano A . 1995 Crit. Rew. Eukariot. Gene Expr. 5: 127–156
MacLachlan TK, Sang N, De Luca A, Puri PL, Levrero M, Giordano A . 1998 J. Cell. Biochem. 71: 467–478
Mancebo H, Lee G, Flygare J, Tomassini J, Luu P, Zhu Y, Blau C, Hazuda D, Price D, Flores O . 1997 Genes Dev. 11: 2633–2644
Marshall N, Peng J, Xie Z, Price D . 1996 J. Biol. Chem. 271: 27176–27183
McGrew MJ, Bogdanova N, Hasegawa K, Hughes SH, Kitsis RN, Rosenthal N . 1996 Mol. Cell. Biol. 16: 4524–4534
Molkentin JD, Olson EN . 1996 Proc. Nat. Acad. Sci. 93: 9366–9373
Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN, Hauschka SD, Lassar AB . 1989 Cell 58: 537–544
Napolitano G, Majello B, Licciardo P, Giordano A, Lania L . 2000 Gene 254: 139–145
Novitch BG, Mulligan GJ, Jacks T, Lassar AB . 1996 J. Cell. Biol. 135: 441–456
Peng J, Zhu Y, Milton JT, Price DH . 1998 Genes Dev. 12: 755–762
Puri PL, Avantaggiati ML, Balsano C, Sang N, Graessmann A, Giordano A, Levrero M . 1997a EMBO J. 16: 369–383
Puri PL, Sartorelli V, Yang XJ, Hamamori Y, Ogryzko VV, Howard BH, Kedes L, Wang JY, Graessmann A, Nakatani Y, Levrero M . 1997b Mol. Cell. 1: 35–45
Puri PL, Wu Z, Zhang P, Wood LD, Bhakta KS, Han J, Feramisco JR, Karin M, Wang JY . 2000 Genes Dev. 14: 574–584
Puri PL, Sartorelli V . 2000 J Cell Physiol. 185: 155–173
Sartorelli V, Huang J, Hamamori Y, Kedes L . 1997 Mol. Cell. Biol. 17: 1010–1026
Sartorelli V, Puri PL, Hamamori Y, Ogryzko V, Chung G, Nakatani Y, Wang JY, Kedes L . 1999 Mol. Cell. 4: 725–734
Sartorelli V, Puri PL . 2001 Front. Biosci. 6: d1073–d1082
Simone C, Giordano A . 2001 Front. Biosci. 6: d1024–d1047
Skapek SX, Rhee J, Kim PS, Novitch BG, Lassar AB . 1996 Mol. Cell. Biol. 16: 7043–7053
Song A, Wang Q, Goebl M, Harrington M . 1998 Mol. Cell. Biol. 18: 4994–4999
Walsh K, Perlman H . 1997 Curr. Opin. Genet. Dev. 7: 597–602
Wei Q, Paterson BM . 2001 FEBS Lett. 490: 171–178
Wei P, Gender ME, Fang SM, Fisher WH, Jones KA . 1998 Cell 92: 451–462
Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S et al . 1991 Science 251: 761–766
Wimmer J, Fujinaga K, Taube R, Cujec TP, Zhu Y, Peng J, Price DH, Peterlin BM . 1999 Virology 255: 182–189
Yang X, Hermann HC, Rice AP . 1996 J. Virol. 70: 4576–4584
Yuan W, Condorelli G, Caruso M, Felsani A, Giordano A . 1996 J. Biol. Chem. 271: 9009–9013
Zhang JM, Wei Q, Zhao X, Paterson BM . 1999a EMBO J. 18: 926–933
Zhang JM, Zhao X, Wei Q, Paterson BM . 1999b EMBO J. 18: 6983–6993
Zhu Y, Pe'ery T, Peng J, Ramanathan Y, Marshall N, Marshall T, Amendt B, Mathews M, Price D . 1997 Genes Dev. 11: 2622–2632
Acknowledgements
We thank Marie Basso for her editorial assistance in the preparation of the manuscript, Dr Margaret Kasten, William Eidenmuller and Dr Pier Paolo Claudio for their comments and helpful suggestions during the preparation of the manuscript and Dr Giuseppe Russo for his technical support. We also thank Drs Bruce M Paterson, Vittorio Sartorelli, Maureen A Harrington, David Price and Franca Cambi for generously providing reagents. This work was supported in part by grants from NIH, Sbarro Institute for Cancer Research and Molecular Medicine (A Giordana) and MURST (G Guanti). C. Simone is supported by a ‘Dottorato di Ricerca in Biologia della Riproduzione Umana ed Animale’ from the University of Bari. C Bellan and L Bagella are supported by a ‘Dottorato di Ricerca in Patologia Diagnostica Quantitativa’ from the University of Siena. G De Falco was partially supported by an AIDS fellowship from ISS and the Sbarro Institute for Cancer Research and Molecular Medicine. A De Luca is the recipient of a grant from the Second University of Naples and a CNR grant. PL Puri is supported by Telethon, Italy, and is an Assistant Telethon Scientist. Finally, we thank Letizia Lavermicocca for her encouragement and support. We dedicate this work to the memory of Professor Angelo Carbonara and Mr Domenico Di Domenico.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simone, C., Stiegler, P., Bagella, L. et al. Activation of MyoD-dependent transcription by cdk9/cyclin T2. Oncogene 21, 4137–4148 (2002). https://doi.org/10.1038/sj.onc.1205493
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205493
Keywords
This article is cited by
-
CDK9 keeps RNA polymerase II on track
Cellular and Molecular Life Sciences (2021)
-
Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled repair
BMC Biochemistry (2011)
-
The myogenic kinome: protein kinases critical to mammalian skeletal myogenesis
Skeletal Muscle (2011)
-
Abrogation of signal-dependent activation of the cdk9/cyclin T2a complex in human RD rhabdomyosarcoma cells
Cell Death & Differentiation (2007)
-
pRb: master of differentiation. Coupling irreversible cell cycle withdrawal with induction of muscle-specific transcription
Oncogene (2006)