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J. Biol. Chem., Vol. 277, Issue 47, 45323-45330, November 22, 2002
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From the Department of Molecular, Cellular, and Developmental
Biology, University of Colorado, Boulder, Colorado 80309
Intracellular calcium levels can have profound
effects on muscle biology via alterations in gene expression. In
particular, intracellular calcium levels increase during muscle
activation and are thought to underlie fast-to-slow shifts in muscle
gene expression. In the present work, we determined that increased intracellular calcium has a significant effect on the activity of the
adult fast myosin heavy chain (MyHC) promoters in the order of MyHC IIa
Intracellular Calcium and Myosin Isoform Transitions
CALCINEURIN AND CALCIUM-CALMODULIN KINASE PATHWAYS REGULATE
PREFERENTIAL ACTIVATION OF THE IIa MYOSIN HEAVY CHAIN PROMOTER*
and
IId/x > IIb. We have identified the pathways by which the
calcium signal mediates increased activation of the MyHC IIa promoter.
Inhibition of calcineurin or calcium-calmodulin kinase greatly
attenuates ionophore-induced activation of the MyHC IIa promoter,
whereas protein kinase C inhibitors have no effect. Inhibition and
overexpression studies with members of the mitogen-activated protein
kinase family reveal roles for MEK1/MEK2 and MEKK1, but not p38 or
phosphatidylinositol 3-kinase. Downstream mediators of these effects
are the activities of the MEF-2 and NFAT transcription factors, whose
binding sites in the MyHC IIa promoter are required for calcium-induced
activation of the MyHC IIa promoter.
*
This work was supported by National Institutes of Health
Grant RO1-GM29090 (to L. A. L.) and an MDA research fellowship grant (to D. L. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular,
Cellular, and Developmental Biology, University of Colorado, Campus Box
347, Boulder, CO 80309-0347. Tel.: 303-492-8371; Fax: 303-492-8907;
E-mail: allendl@stripe.colorado.edu.
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