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(Received for publication, March 1, 1996, and in revised form, August 9, 1996)
From the Medical Research Council Group in Molecular Biology of
Membranes, the Department of Biochemistry, University of Alberta,
Edmonton, Alberta, T6G 2S2 Canada and the ¶ Department of Anatomy
and Cell Biology, University of Toronto,
Toronto, Ontario, M5S 1A8 Canada
Calreticulin is a ubiquitously
expressed Ca2+-binding protein of the endoplasmic reticulum
(ER), which inhibits DNA binding in vitro and
transcriptional activation in vivo by steroid hormone receptors. Transient transfection assays were carried out to
investigate the effects of different intracellular targeting of
calreticulin on transactivation mediated by glucocorticoid receptor.
BSC40 cells were transfected with either calreticulin expression vector (ER form of calreticulin) or calreticulin expression vector encoding calreticulin minus leader peptide, resulting in cytoplasmic
localization of the recombinant protein. Transfection of BSC40 cells
with calreticulin expression vector encoding the ER form of the protein
led to 40-50% inhibition of the dexamethasone-sensitive stimulation
of luciferase expression. However, in a similar experiment, but using
the calreticulin expression vector encoding cytoplasmic calreticulin,
dexamethasone-stimulated activation of the luciferase reporter gene was
inhibited by only 10%. We conclude that the ER, but not cytosolic,
form of calreticulin is responsible for inhibition of glucocorticoid
receptor-mediated gene expression. These effects are specific to
calreticulin, since overexpression of the ER lumenal proteins (BiP,
ERp72, or calsequestrin) has no effect on glucocorticoid-sensitive gene
expression. The N domain of calreticulin binds to the DNA binding
domain of the glucocorticoid receptor in vitro; however, we
show that the N+P domain of calreticulin, when synthesized without the
ER signal sequence, does not inhibit glucocorticoid receptor function
in vivo. Furthermore, expression of the N domain of
calreticulin and the DNA binding domain of glucocorticoid receptor as
fusion proteins with GAL4 in the yeast two-hybrid system revealed that calreticulin does not interact with glucocorticoid receptor under these
conditions. We conclude that calreticulin and glucocorticoid receptor
may not interact in vivo and that the
calreticulin-dependent modulation of the glucocorticoid
receptor function may therefore be due to a
calreticulin-dependent signaling from the ER.
Volume 271, Number 46,
Issue of November 15, 1996
pp. 29436-29445
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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