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PMID: 10805738 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps.

Molecular and cellular biology ·Vol. 20 ·No. 11 ·2000-06-00 ·Pages 3951-64

Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY, Puri PL

Abstract

The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogen-activated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun-N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38alpha(-/-) embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes.

MeSH Terms
Animals Cell Differentiation Cell Line Cells, Cultured DNA-Binding Proteins/metabolism Enzyme Activation Humans Insulin-Like Growth Factor I/metabolism Isoenzymes/metabolism MADS Domain Proteins MEF2 Transcription Factors Mice Mitogen-Activated Protein Kinases/metabolism MyoD Protein/metabolism Myogenic Regulatory Factors/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Signal Transduction Transcription Factors/metabolism Transcription, Genetic p38 Mitogen-Activated Protein Kinases
Chemicals
DNA-Binding Proteins Isoenzymes MADS Domain Proteins MEF2 Transcription Factors MEF2A protein, human MEF2C protein, human Mef2a protein, mouse Mef2c protein, mouse MyoD Protein Myogenic Regulatory Factors Transcription Factors Insulin-Like Growth Factor I Phosphatidylinositol 3-Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wu Z
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093-0322, USA.
Woodring P J
Bhakta K S
Tamura K
Wen F
Feramisco J R
Karin M
Wang J Y
Puri P L
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.11.3951-3964.2000
Published
2000-06-00
Pages
3951-64
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85749
Subset
IM
Grants
NCI NIH HHS · R01 CA058320 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.11.3951-3964.2000 PMC Full Text View journal details
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