HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/C1887    most recent 00506.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Alfieri, C. M. Articles by Yutzey, K. E. Search for Related Content PubMed PubMed Citation Articles by Alfieri, C. M. Articles by Yutzey, K. E.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

Developmental regulation of the mouse IGF-I exon 1 promoter region by calcineurin activation of NFAT in skeletal muscle

Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio

Submitted 29 September 2006 ; accepted in final form 11 January 2007

Skeletal muscle development and growth are regulated through multiple signaling pathways that include insulin-like growth factor I (IGF-I) and calcineurin activation of nuclear factor of activated T cell (NFAT) transcription factors. The developmental regulation and molecular mechanisms that control IGF-I gene expression in murine embryos and in differentiating C2C12 skeletal myocytes were examined. IGF-I is expressed in developing skeletal muscle, and its embryonic expression is significantly reduced in embryos lacking both NFATc3 and NFATc4. During development, the IGF-I exon 1 promoter is active in multiple organ systems, including skeletal muscle, whereas the alternative exon 2 promoter is expressed predominantly in the liver. The IGF-I exon 1 promoter flanking sequence includes two highly conserved regions that contain NFAT consensus binding sequences. One of these conserved regions contains a calcineurin/NFAT-responsive regulatory region that is preferentially activated by NFATc3 in C2C12 skeletal muscle cells and NIH3T3 fibroblasts. This NFAT-responsive region contains three clustered NFAT consensus binding sequences, and mutagenesis experiments demonstrated the requirement for two of these in calcineurin or NFATc3 responsiveness. Chromatin immunoprecipitation analyses demonstrated that endogenous IGF-I genomic sequences containing these conserved NFAT binding sequences interact preferentially with NFATc3 in C2C12 cells. Together, these experiments demonstrated that a NFAT-rich regulatory element in the IGF-I exon 1 promoter flanking region is responsive to calcineurin signaling and NFAT activation in skeletal muscle cells. The identification of a calcineurin/NFAT-responsive element in the IGF-I gene represents a potential mechanism of intersection of these signaling pathways in the control of muscle development and homeostasis.

insulin-like growth factor I; nuclear factor of activated T cells c3; skeletal muscle; gene regulation

This article has been cited by other articles:

				N. Stupka, J. D. Schertzer, R. Bassel-Duby, E. N. Olson, and G. S. Lynch Stimulation of calcineurin A{alpha} activity attenuates muscle pathophysiology in mdx dystrophic mice Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R983 - R992. [Abstract] [Full Text] [PDF]

				A. M. Fernandez, S. Fernandez, P. Carrero, M. Garcia-Garcia, and I. Torres-Aleman Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals J. Neurosci., August 15, 2007; 27(33): 8745 - 8756. [Abstract] [Full Text] [PDF]