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Originally published as MBC in Press, 10.1091/mbc.E07-09-0886 on March 19, 2008

Vol. 19, Issue 6, 2509-2519, June 2008

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Calcium Regulation of Myogenesis by Differential Calmodulin Inhibition of Basic Helix-Loop-Helix Transcription Factors

Jannek Hauser, Juha Saarikettu, and Thomas Grundström

Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden

Submitted September 12, 2007; Revised February 19, 2008; Accepted March 6, 2008
Monitoring Editor: Marianne Bronner-Fraser

The members of the MyoD family of basic helix-loop-helix (bHLH) transcription factors are critical regulators of skeletal muscle differentiation that function as heterodimers with ubiquitously expressed E-protein bHLH transcription factors. These heterodimers must compete successfully with homodimers of E12 and other E-proteins to enable myogenesis. Here, we show that E12 mutants resistant to Ca2+-loaded calmodulin (CaM) inhibit MyoD-initiated myogenic conversion of transfected fibroblasts. Ca2+ channel blockers reduce, and Ca2+ stimulation increases, transcription by coexpressed MyoD and wild-type E12 but not CaM-resistant mutant E12. Furthermore, CaM-resistant E12 gives lower MyoD binding and higher E12 binding to a MyoD-responsive promoter in vivo and cannot rescue myogenic differentiation that has been inhibited by siRNA against E12 and E47. Our data support the concept that Ca2+-loaded CaM enables myogenesis by inhibiting DNA binding of E-protein homodimers, thereby promoting occupancy of myogenic bHLH protein/E-protein heterodimers on promoters of myogenic target genes.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-09-0886) on March 19, 2008.

Address correspondence to: Thomas Grundström (Thomas.Grundstrom{at}molbiol.umu.se).






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