CHOP-Dependent stress-inducible expression of a novel form of carbonic anhydrase VI.
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.
Sok
J
J
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, USA.
Wang
X Z
XZ
Batchvarova
N
N
Kuroda
M
M
Harding
H
H
Ron
D
D
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D019556:COS Cells; D002256:Carbonic Anhydrases / Q000235:genetics*; D002461:Cell Line, Transformed; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D002256:Carbonic Anhydrases