Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins.
Differentiation of skeletal muscle cells is inhibited by the cyclic AMP (cAMP) signal transduction pathway. Here we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) can substitute for cAMP and suppress muscle-specific transcription by silencing the activity of the MyoD family of regulatory factors, which includes MyoD, myogenin, myf5, and MRF4. Repression by the PKA catalytic (C) subunit is directed at the consensus sequence CANNTG, the target for DNA binding and transcriptional activation by these myogenic regulators. Phosphopeptide mapping of myogenin in vitro and in vivo revealed two PKA phosphorylation sites, both within the basic region. However, repression of myogenin function by PKA does not require direct phosphorylation of these sites but instead involves an indirect mechanism with one or more intermediate steps. Regulation of the transcriptional activity of the MyoD family by modulation of the cAMP signaling pathway may account for the inhibitory effects of certain peptide growth factors on muscle-specific gene expression and may also determine the responsiveness of different cell types to myogenic conversion by these myogenic regulators.
Li
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Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Heller-Harrison
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Czech
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Olson
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EN
D000595:Amino Acid Sequence; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000166:cytology* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017570:MyoD Protein; D018008:Myogenin; D009928:Organ Specificity / Q000235:genetics; D010449:Peptide Mapping; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic
D009124:Muscle Proteins; D017570:MyoD Protein; D018008:Myogenin; D014157:Transcription Factors; D011494:Protein Kinases