p38 Mitogen-activated Protein Kinase Pathway Promotes Skeletal Muscle Differentiation
PARTICIPATION OF THE MEF2C TRANSCRIPTION FACTOR*
- From the Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Abstract
Differentiation of muscle cells is regulated by extracellular growth factors that transmit largely unknown signals into the cells. Some of these growth factors induce mitogen-activated protein kinase (MAPK) cascades within muscle cells. In this work we show that the kinase activity of p38 MAPK is induced early during terminal differentiation of L8 cells. Addition of a specific p38 inhibitor SB 203580 to myoblasts blocked their fusion to multinucleated myotubes and prevented the expression of MyoD and MEF2 family members and myosin light chain 2. The expression of MKK6, a direct activator of p38, or of p38 itself enhanced the activity of MyoD in converting 10T1/2 fibroblasts to muscle, whereas treatment with SB 203580 inhibited MyoD. Several lines of evidence suggesting that the involvement of p38 in MyoD activity is mediated via its co-activator MEF2C, a known substrate of p38, are presented. In these experiments we show that MEF2C protein and MEF2-binding sites are necessary for the p38 MAPK pathway to regulate the transcription of muscle creatine kinase reporter gene. Our results indicate that the p38 MAPK pathway promotes skeletal muscle differentiation at least in part via activation of MEF2C.
Footnotes
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↵* This work was supported by a United States-Israel Binational Foundation grant, by an Israel Cancer Association grant, and by funds from the Rappaport Foundation for Medical Research and the Foundation for Promotion of Research in the Technion, Israel Institute of Technology.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ These authors contributed equally to the work.
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↵§ To whom correspondence should be addressed: Dept. of Biochemistry, Faculty of Medicine, Technion-Israel Inst. of Technology, P.O. Box 9649, Haifa 31096, Israel. Tel.: 972-4-8295-287; Fax: 972-4-8535-773; E-mail: Bengal{at}tx.technion.ac.il.
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↵2 J. McDermott, personal communication.
- Abbreviations:
- MAPK
-
mitogen-activated protein kinase
- MCK
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muscle creatine kinase
- ER
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estrogen receptor
- ERK
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extracellular signal-regulated protein kinase
- DM
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differentiation medium
- CAT
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chloramphenicol acetyltransferase
- GST
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glutathione S-transferase
- PAGE
-
polyacrylamide gel electrophoresis
- MHC
-
myosin heavy chain
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- Received June 10, 1998.
- Revision received November 6, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
