Miner, Jeffrey H. and Wold, Barbara J. (1991) c-myc inhibition of MyoD and myogenin-initiated myogenic differentiation. Molecular and Cellular Biology, 11 (5). pp. 2842-2851. ISSN 0270-7306. http://resolver.caltech.edu/CaltechAUTHORS:20120423-113016430
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In vertebrate development, a prominent feature of several cell lineages is the coupling of cell cycle regulation with terminal differentiation. We have investigated the basis of this relationship in the skeletal muscle lineage by studying the effects of the proliferation-associated regulator, c-myc, on the differentiation of MyoD-initiated myoblasts. Transient cotransfection assays in NIH 3T3 cells using MyoD and c-myc expression vectors demonstrated c-myc suppression of MyoD-initiated differentiation. A stable cell system was also developed in which MyoD expression was constitutive, while myc levels could be elevated conditionally. Induction of this conditional c-myc suppressed myogenesis effectively, even in the presence of MyoD. c-myc suppression also prevented up-regulation of a relative of MyoD, myogenin, which is normally expressed at the onset of differentiation in all muscle cell lines examined and may be essential for differentiation. Additional experiments tested whether failure to differentiate in the presence of myc could be overcome by providing myogenin ectopically. Cotransfection of c-myc with myogenin, MyoD, or a mixture of myogenin and MyoD showed that neither myogenin alone nor myogenin plus MyoD together could bypass the c-myc block. The effects of c-myc were further dissected by showing that c-myc can inhibit differentiation independently of Id, a negative regulator of muscle differentiation. These results lead us to propose that c-myc and Id constitute independent negative regulators of muscle differentiation, while myogenin and any of the other three related myogenic factors (MyoD, Myf-5, and MRF4/herculin/Myf-6) act as positive regulators.
|Additional Information:||© 1991 American Society for Microbiology. Received 3 December 1990; Accepted 19 February 1991. We are indebted to A. Lassar, R. Davis, and H. Weintraub for the MyoD cDNA and helpful suggestions; to R. Benezra and H. Weintraub for the Id cDNA; to W. Wright and E. Olson for rat and mouse myogenin cDNAs, respectively; to S. Tavtigian for the MT-myc cell line; to S. Hauschka and J. Johnson for immune reagents and MM14 and C2C12 cell lines; to R. Miake-Lye for the pECE vector; and to K. Lee for help with cell counting. We also thank D. Anderson, N. Davidson, P. Stemnberg, and members of the Wold group for helpful insights during the course of this work and for comments on the manuscript. J.H.M. was supported by a National Science Foundation Graduate Fellowship and by National Research Service Award GM07616 from the National Institute of General Medical Sciences. This work was supported by grants to B.W. from the National Institutes of Health, the Rita Allen Foundation, and the Muscular Dystrophy Association.|
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|Deposited By:||Tony Diaz|
|Deposited On:||23 Apr 2012 21:40|
|Last Modified:||26 Dec 2012 15:06|
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