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J. Biol. Chem., Vol. 277, Issue 51, 49776-49781, December 20, 2002
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From the Department of Microbiology-Immunology, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois 60611
Recent studies have revealed that the
calcium-dependent serine/threonine phosphatase calcineurin
mediates the effects of intracellular calcium in many different cell
types. In this study we investigated the role of calcineurin in the
regulation of adipocyte differentiation. We found that the specific
calcineurin inhibitors cyclosporin A and FK506 overcame the
antiadipogenic effect of calcium ionophore on the differentiation of
3T3-L1 preadipocytes. This finding suggests that calcineurin is
responsible for mediating the previously documented Ca2+-dependent inhibition of
adipogenesis. We further demonstrate that the expression of a
constitutively active calcineurin mutant potently inhibits the ability
of 3T3-L1 cells to undergo adipocyte differentiation by preventing
expression of the proadipogenic transcription factors peroxisome
proliferator-activated receptor
Calcineurin Mediates the
Calcium-dependent Inhibition of Adipocyte Differentiation
in 3T3-L1 Cells*
(PPAR) and
CCAAT/enhancer-binding protein 
(C/EBP). This calcineurin-mediated block in adipocyte differentiation is rescued by
ectopic expression of PPAR1. Finally, we demonstrate that inhibition
of endogenous calcineurin activity with either FK506 or a specific
calcineurin inhibitory peptide enhances differentiation of 3T3-L1 cells
in response to suboptimal adipogenic stimuli, suggesting that
endogenous calcineurin activity normally sets a signaling threshold
that antagonizes efficient adipocyte differentiation. Collectively,
these data indicate that calcineurin acts as a
Ca2+-dependent molecular switch that negatively
regulates commitment to adipocyte differentiation by preventing the
expression of critical proadipogenic transcription factors.
*
This work was supported in part by a Gramm travel fellowship
award from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (to J. W. N.) and by National Institutes of
Health Grant R29 GM55292 (to N. A. C.).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
Microbiology-Immunology, Northwestern University, 303 E. Chicago
Ave., Chicago, IL 60611. Tel.: 312-503-8233; Fax:
312-503-1339; E-mail: n-clipstone@northwestern.edu.
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