MEKK1 Signaling through p38 Leads to Transcriptional Inactivation of E47 and Repression of Skeletal Myogenesis

Activation of the Raf kinase signal transduction pathway in skeletal myoblasts causes a complete cessation of myofiber formation and muscle gene expression. The negative impacts of the signaling pathway are realized through downstream activation of mitogen and extracellular kinase (MEK) phosphorylat...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-07, Vol.279 (30), p.30966-30972
Main Authors: Page, Jeanine L, Wang, Xu, Sordillo, Lorraine M, Johnson, Sally E
Format: Article
Language:English
Subjects:
Animals
Cell Line
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
In Vitro Techniques
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 1
MAP Kinase Kinase Kinases - metabolism
MAP Kinase Signaling System
Mice
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Muscle Development - genetics
Muscle Development - physiology
Muscle, Skeletal - growth & development
p38 Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-raf - metabolism
TCF Transcription Factors
Transcription Factor 7-Like 1 Protein
Transcription Factors - antagonists & inhibitors
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
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Summary:Activation of the Raf kinase signal transduction pathway in skeletal myoblasts causes a complete cessation of myofiber formation and muscle gene expression. The negative impacts of the signaling pathway are realized through downstream activation of mitogen and extracellular kinase (MEK) phosphorylation-dependent events and MEK-independent signal transmission. MEKK1, a kinase that can physically associate with Raf, may contribute to the MEK-independent signaling in response to elevated Raf activity. Myogenic cells overexpressing activated Raf and kinase-defective MEKK1 remain differentiation-defective, suggesting that MEKK1 does not contribute to the inhibitory actions of Raf. However, constitutive activation of MEKK1 dramatically inhibits biochemical and morphological measures of muscle formation. MEKK1 inhibits MyoD-directed transcriptional activity without altering the ability of the protein to form heterodimers with E2A proteins or bind DNA. By contrast, the transcriptional activity of E47, the preferred dimer partner of the myogenic regulatory factors, is severely compromised by MEKK1-initiated signaling. Inhibition of MEK1/2 and JNK1/2 function did not reinstate E47-directed transcription, indicating that these two downstream kinases likely are not involved in the MEKK1-controlled transcriptional block. Inhibition of p38 signaling overcame the negative effects exerted by MEKK1 on the amino terminus of E47. Closer examination indicates that E47 is phosphorylated in vitro by p38, and deletion analysis predicts that the critical amino acid(s) phosphorylated by p38 lie outside of the minimal transcriptional activation domains. Thus, modification of E47 by p38 likely disrupts higher order protein complex formation that is necessary for muscle gene transcription.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M402224200