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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/EBPbeta 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/ebpbeta -/- cells by exogenous C/EBPbeta 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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