Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 292, Issue 5, Pages C1887-C1894Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00506.2006
Keywords
insulin-like growth factor I; nuclear factor of activated T cells c3; skeletal muscle; gene regulation
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Funding
- NHLBI NIH HHS [P01-HL-069779] Funding Source: Medline
- NIEHS NIH HHS [T32-ES-07051] Funding Source: Medline
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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 immuno-precipitation 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.
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