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Activation of MyoD-dependent transcription by cdk9/cyclin T2

Oncogene volume 21, pages 4137–4148 (2002)Cite this article

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.

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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.

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Authors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, 19122, Pennsylvania, PA, USA

    Cristiano Simone, Luigi Bagella, Cristiana Bellan, Giulia De Falco, Antonio De Luca & Antonio Giordano

  2. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, PA, USA

    Cristiano Simone, Peter Stiegler, Luigi Bagella, Bruna Pucci & Antonio Giordano

  3. Department of Internal Medicine and Public Medicine, Division of Medical Genetics, University of Bari, Bari, 70124, Italy

    Cristiano Simone & Ginevra Guanti

  4. Institute of Pathologic Anatomy and Histology, University of Siena, Siena, 53100, Italy

    Luigi Bagella & Cristiana Bellan

  5. Institute of Topographical Anatomy, School of Medicine, 2nd University of Naples, Naples, 80138, Italy

    Antonio De Luca

  6. Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome ‘La Sapienza’, 0061, Rome, Italy

    Pier Lorenzo Puri

  7. Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, 92093, California, CA, USA

    Pier Lorenzo Puri

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  1. Cristiano Simone
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Correspondence to Antonio Giordano.

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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

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