Article
- The EMBO Journal (2005) 24, 974 - 984
- doi:10.1038/sj.emboj.7600528
Published online: 17 February 2005
Subject Categories:
E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription
Frederic Lluís1, Esteban Ballestar2,a, Mònica Suelves1,a, Manel Esteller2 and Pura Muñoz-Cánoves1
- Center for Genomic Regulation (CRG), Program on Differentiation and Cancer, Barcelona, Spain
- Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
Correspondence to:
Pura Muñoz-Cánoves, Center for Genomic Regulation (CRG), Program on Differentiation and Cancer, Passeig Maritim, 37-49, 08003 Barcelona, Spain. Tel.: +34 93 224 09 33; Fax: +34 93 224 08 99; E-mail: pura.munoz@crg.es
aThese authors contributed equally to this work
Received 11 August 2004; Accepted 29 November 2004
Abstract
Selective recognition of the E-box sequences on muscle gene promoters by heterodimers of myogenic basic helix–loop–helix (bHLH) transcription factors, such as MyoD, with the ubiquitous bHLH proteins E12 and E47 is a key event in skeletal myogenesis. However, homodimers of MyoD or E47 are unable of binding to and activating muscle chromatin targets, suggesting that formation of functional MyoD/E47 heterodimers is pivotal in controlling muscle transcription. Here we show that p38 MAPK, whose activity is essential for myogenesis, regulates MyoD/E47 heterodimerization. Phosphorylation of E47 at Ser140 by p38 induces MyoD/E47 association and activation of muscle-specific transcription, while the nonphosphorylatable E47 mutant Ser140Ala fails to heterodimerize with MyoD and displays impaired myogenic potential. Moreover, inhibition of p38 activity in myocytes precludes E47 phosphorylation at Ser140, which results in reduced MyoD/E47 heterodimerization and inefficient muscle differentiation, as a consequence of the impaired binding of the transcription factors to the E regulatory regions of muscle genes. These findings identify a novel pro-myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis.
Keywords:
- E protein,
- MRF,
- muscle differentiation,
- p38 MAPK,
- transcription
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