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J. Biol. Chem., Vol. 279, Issue 42, 43625-43633, October 15, 2004

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E2F-1 Regulates the Expression of a Subset of Target Genes during Skeletal Myoblast Hypertrophy^*

Myint Hlaing, Paul Spitz, Krishnan Padmanabhan, Blanca Cabezas¶, Christopher S. Barker¶, and Harold S. Bernstein||**

From the Cardiovascular Research Institute, the ^||Cancer Center, and the ^**Department of Pediatrics, University of California, San Francisco, California 94143 and the ^¶Genomics Laboratory, The J. David Gladstone Institutes, San Francisco, California 94103

Cellular hypertrophy, or growth without division, is an adaptive response to various physiological and pathological stimuli in postmitotic muscle. We demonstrated previously that angiotensin II stimulates hypertrophy in C2C12 myoblasts by transient activation of the cyclin-dependent kinase 4 complex, subsequent phosphorylation of retinoblastoma protein, release of histone deacetylase 1 from the retinoblastoma protein inhibitory complex, and partial activation of the transcription factor E2F-1. These observations led us to propose a model in which partial inactivation of the retinoblastoma protein complex leads to the derepression of a subset of E2F-1 targets necessary for cell growth without division during hypertrophy. We now present data that support this model and suggest the mechanism by which E2F-1 regulates hypertrophy. We examined expression profiles of angiotensin II-stimulated myoblasts and identified a subset of E2F-1 target genes that are specifically regulated during the hypertrophic response. We showed that the expression of E2F-1 targets involved in G₁/S transit, DNA replication, and mitosis is not altered during the hypertrophic response, while the expression of E2F-1-regulated genes controlling early G₁ progression, cytoskeletal organization, protein synthesis, mitochondrial function, and programmed cell death is up-regulated. Furthermore, we demonstrated that activation of cytochrome c oxidase genes occurs during the development of hypertrophy and that cytochrome c oxidase IV is a direct transcriptional target of E2F-1. These studies demonstrated that E2F-1 activity at specific promoters is dependent on physiological circumstances and that E2F-1 should be considered a potential target in the treatment of pathologic hypertrophy.

Received for publication, July 26, 2004

^* This work was supported in part by National Institutes of Health Grants HL62174 (to H. S. B.) and HL72301 supporting the UCSF NHLBI, National Institutes of Health Shared Microarray Facility. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The array data were deposited in Gene Expression Omnibus (GEO) under accession number GSE1592.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

Supported by National Institutes of Health Grant F32 HL 72571.

An established investigator of the American Heart Association. To whom correspondence should be addressed: University of California, 505 Parnassus Ave., Box 0130, San Francisco, CA 94143-0130. Fax: 415-514-0235; E-mail: hsbernstein{at}pedcard.ucsf.edu.

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