© 2000 American Heart Association, Inc.
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Independent Signals Control Expression of the Calcineurin Inhibitory Proteins MCIP1 and MCIP2 in Striated Muscles
From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to R. Sanders Williams, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, NB11.200, Dallas, TX 75390-8573. E-mail williams{at}ryburn.swmed.edu
Abstract—Calcineurin,
a calcium/calmodulin-regulated protein phosphatase, modulates gene
expression in cardiac and skeletal muscles during development and in
remodeling responses such as cardiac hypertrophy that are evoked by
environmental stresses or disease. Recently, we identified two genes
encoding proteins (MCIP1 and MCIP2) that are enriched in striated
muscles and that interact with calcineurin to inhibit its enzymatic
activity. In the present study, we show that expression of MCIP1 is
regulated by calcineurin activity in hearts of mice with cardiac
hypertrophy, as well as in cultured skeletal myotubes. In contrast,
expression of MCIP2 in the heart is not altered by activated
calcineurin but responds to thyroid hormone, which has no effect on
MCIP1. A 
900-bp intragenic segment located between exons 3 and 4 of
the MCIP1 gene functions as an alternative promoter that responds to
calcineurin. This region includes a dense cluster of 15 consensus
binding sites for NF-AT transcription factors. Because MCIP proteins
can inhibit calcineurin, these results suggest that MCIP1 participates
in a negative feedback circuit to diminish potentially deleterious
effects of unrestrained calcineurin activity in cardiac and skeletal
myocytes. Inhibitory effects of MCIP2 on calcineurin activity may be
pertinent to gene switching events driven by thyroid hormone in
striated muscles. The full text of this article is available at
http://www.circresaha.org.
Key Words: calcineurin • hypertrophy • gene transcription • thyroid hormone
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