Abstract
Intracellular calcium is one of the important signals that initiates the myogenic program. The calcium-activated phosphatase calcineurin is necessary for the nuclear import of the nuclear factor of activated T cell (NFAT) family members, which interact with zinc finger GATA transcription factors. Whereas GATA-6 plays a role in the maintenance of the differentiated phenotype in vascular smooth muscle cells (VSMCs), it is unknown whether the calcineurin pathway is associated with GATA-6 and plays a role in the differentiation of VSMCs. The smooth muscle-myosin heavy chain (Sm-MHC) gene is a downstream target of GATA-6, and provides a highly specific marker for differentiated VSMCs. Using immunoprecipitation Western blotting, we showed that NFATc1 interacted with GATA-6. Consistent with this, NFATc1 further potentiated GATA-6-activated Sm-MHC transcription. Induction of VSMCs to the quiescent phenotype caused nuclear translocation of NFATc1. In differentiated VSMCs, blockage of calcineurin down-regulated the amount of GATA-6-DNA binding as well as the expression of Sm-MHC and its transcriptional activity. These findings demonstrate that the calcineurin pathway is associated with GATA-6 and is required for the maintenance of the differentiated phenotype in VSMCs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / drug effects
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Actins / genetics
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Actins / metabolism
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Animals
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COS Cells
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Calcineurin / drug effects
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Calcineurin / genetics
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Calcineurin / metabolism*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Division / drug effects
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Cell Division / physiology
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Cell Nucleus / drug effects
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Common Variable Immunodeficiency
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DNA / drug effects
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DNA / metabolism
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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GATA6 Transcription Factor
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Humans
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Immunohistochemistry
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / growth & development*
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Muscle, Smooth, Vascular / metabolism*
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Myosin Heavy Chains / drug effects
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Myosin Heavy Chains / genetics
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Myosin Heavy Chains / metabolism
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NFATC Transcription Factors
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Nuclear Proteins*
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Phenotype
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / physiology
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Protein Transport / drug effects
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Protein Transport / genetics
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology*
Substances
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Actins
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DNA-Binding Proteins
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GATA6 Transcription Factor
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GATA6 protein, human
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NFATC Transcription Factors
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NFATC1 protein, human
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Nuclear Proteins
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Transcription Factors
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DNA
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Calcineurin
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Myosin Heavy Chains