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Molecular and Cellular Biology, April 2008, p. 2446-2459, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.00980-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CREB-1{alpha} Is Recruited to and Mediates Upregulation of the Cytochrome c Promoter during Enhanced Mitochondrial Biogenesis Accompanying Skeletal Muscle Differentiation{triangledown} ,{dagger}

Andras Franko,1,2 Sabine Mayer,3 Gerald Thiel,3 Ludovic Mercy,4 Thierry Arnould,4 Hue-Tran Hornig-Do,1 Rudolf J. Wiesner,1,2* and Steffi Goffart1

Institute of Vegetative Physiology, Medical Faculty, University of Köln, Köln, Germany,1 Center for Molecular Medicine Cologne, University of Köln, Köln, Germany,2 Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Homburg, Germany,3 Unité de Biochimie et Biologie Cellulaire, University of Namur (FUNDP), Namur, Belgium4

Received 4 June 2007/ Returned for modification 23 July 2007/ Accepted 15 January 2008

To further understand pathways coordinating the expression of nuclear genes encoding mitochondrial proteins, we studied mitochondrial biogenesis during differentiation of myoblasts to myotubes. This energy-demanding process was accompanied by a fivefold increase of ATP turnover, covered by an eightfold increase of mitochondrial activity. While no change in mitochondrial DNA copy number was observed, mRNAs as well as proteins for nucleus-encoded cytochrome c, cytochrome c oxidase subunit IV, and mitochondrial transcription factor A (TFAM) increased, together with total cellular RNA and protein levels. Detailed analysis of the cytochrome c promoter by luciferase reporter, binding affinity, and electrophoretic mobility shift assays as well as mutagenesis studies revealed a critical role for cyclic AMP responsive element binding protein 1 (CREB-1) for promoter activation. Expression of two CREB-1 isoforms was observed by using specific antibodies and quantitative reverse transcription-PCR, and a shift from phosphorylated CREB-1{Delta} in myoblasts to phosphorylated CREB-1{alpha} protein in myotubes was shown, while mRNA ratios remained unchanged. Chromatin immunoprecipitation assays confirmed preferential binding of CREB-1{alpha} in situ to the cytochrome c promoter in myotubes. Overexpression of constitutively active and dominant-negative forms supported the key role of CREB-1 in regulating the expression of genes encoding mitochondrial proteins during myogenesis and probably also in other situations of enhanced mitochondrial biogenesis.

* Corresponding author. Mailing address: Institute of Vegetative Physiology, Medical Faculty, University of Köln, Robert-Koch-Strasse 39, 50931 Köln, Germany. Phone: 492214783610. Fax: 492214783538. E-mail: rudolf.wiesner{at}uni-koeln.de

{triangledown} Published ahead of print on 28 January 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2008, p. 2446-2459, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.00980-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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