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J. Biol. Chem., Vol. 276, Issue 18, 15018-15024, May 4, 2001
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From the Department of Pharmacology, University of Vermont,
Burlington, Vermont 05405
The transcription factor NFAT (nuclear
factor of activated T-cells) plays a central role in mediating
Ca2+-dependent gene transcription in a
variety of cell types. Sustained increases in intracellular calcium
concentration ([Ca2+]i) are
presumed to be required for NFAT dephosphorylation by the
Ca2+/calmodulin-dependent protein calcineurin and
its subsequent nuclear translocation. Here, we provide the first
identification and characterization of NFAT in native smooth muscle,
showing that NFAT4 is the predominant isoform detected by reverse
transcriptase-polymerase chain reaction and Western blot analysis. PDGF
induces NFAT4 translocation in smooth muscle, leading to an increase in
NFAT transcriptional activity. NFAT4 activation by PDGF depends on
Ca2+ entry through voltage-dependent
Ca2+ channels, because its nuclear accumulation is
prevented by the Ca2+ channel blocker nisoldipine and the
K+ channel opener pinacidil. Interestingly, elevation of
[Ca2+]i by membrane
depolarization or ionomycin treatment are not effective stimuli for
NFAT4 nuclear accumulation, indicating that Ca2+ influx is
necessary but not sufficient for NFAT4 activation. In contrast,
membrane depolarization readily activates the
Ca2+-dependent transcription factor CREB
(cAMP-responsive element-binding protein). The calcineurin blockers CsA
and FK506 also prevented the PDGF-induced NFAT4 nuclear localization.
These results indicate that both the nature of the calcium
signal and PDGF-induced modulation of nuclear import-export of NFAT are
critical for NFAT4 activation in this tissue.
NFAT4 Movement in Native Smooth Muscle
A ROLE FOR DIFFERENTIAL Ca2+ SIGNALING*
,,
*
This work was supported by Grants HL44455, HL63722, DDK53832
(to M. T. N.) and NIH Postdoctoral Cardiovascular Training Grant HL07647-12 (to D. C. H-E.), and a Graduate Research Supplement to
HL44455 (to A. S. S.) as well as by grants from the Swedish Medical
Research Council, K. & A. Wallenberg, and Dr. P. Håkansson Foundation (to M. F. G.).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.
These authors contributed equally to this work.
§
To whom correspondence should be addressed. Tel.: 802-656-2500;
Fax: 802- 656-4523; E-mail: nelson@salus.med.uvm.edu.
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