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Molecular and Cellular Biology, January 1999, p. 495-504, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
CHOP-Dependent Stress-Inducible Expression of a
Novel Form of Carbonic Anhydrase VI
John
Sok,
Xiao-Zhong
Wang,
Nikoleta
Batchvarova,
Masahiko
Kuroda,
Heather
Harding, and
David
Ron*
Skirball Institute of Biomolecular Medicine,
Departments of Medicine and Cell Biology, and Kaplan Cancer Center,
New York University Medical Center, New York, New York 10016
Received 27 May 1998/Returned for modification 15 July
1998/Accepted 10 September 1998
CHOP (also called GADD153) is a stress-inducible nuclear protein
that dimerizes with members of the C/EBP family of transcription factors and was initially identified as an inhibitor of C/EBP binding
to classic C/EBP target genes. Subsequent experiments suggested a role
for CHOP-C/EBP heterodimers in positively regulating gene expression;
however, direct evidence that this is the case has so far not been
uncovered. Here we describe the identification of a positively
regulated direct CHOP-C/EBP target gene, that encoding murine carbonic
anhydrase VI (CA-VI). The stress-inducible form of the gene is
expressed from an internal promoter and encodes a novel intracellular
form of what is normally a secreted protein. Stress-induced expression
of CA-VI is both CHOP and C/EBP
dependent in that it does not occur in cells deficient in either gene.
A CHOP-responsive element was mapped to the inducible
CA-VI promoter, and in vitro footprinting revealed binding
of CHOP-C/EBP heterodimers to that site. Rescue of CA-VI
expression in c/ebp
/
cells by exogenous
C/EBP
and a shorter, normally inhibitory isoform of the protein
known as LIP suggests that the role of the C/EBP partner is limited to
targeting the CHOP-containing heterodimer to the response element and
points to a preeminent role for CHOP in CA-VI induction during stress.
*
Corresponding author. Mailing address: Skirball
Institute of Biomolecular Medicine, New York University Medical Center,
New York, NY 10016. Phone: (212) 263-7786. Fax: (212) 263-8951. E-mail: ron{at}saturn.med.nyu.edu.
Molecular and Cellular Biology, January 1999, p. 495-504, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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