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Volume 271, Number 50, Issue of December 13, 1996 pp. 31869-31877
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Characterization of the cAMP Response Element of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Promoter

(Received for publication, August 23, 1996)

From the Department of Pharmacology, University of Washington, Seattle, Washington 98195-7750

A dominant negative inhibitor of the cAMP-dependent protein kinase has been shown to inhibit the basal expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the human colon carcinoma cell line, T84. A functional cAMP response element (CRE) was localized at 48 in the CFTR promoter, and we have analyzed the interactions of this regulatory region with transcription factors. An adjacent inverted CCAAT element (Y box) at position 60 was also investigated. Mutation of the CRE or the Y box decreases the activity of the promoter in transient transfections of T84 or JEG-3 cells. Electrophoretic mobility shift assays demonstrate that CRE-binding protein (CREB) binds to the CFTR CRE with high affinity and independently of the adjacent Y box and that the CFTR CRE binds CREB and activating transcription factor-1 in nuclear extracts of T84 and CaLu-3 cells. In transient transfections of JEG-3 cells, activation of the CFTR promoter is blocked by a dominant negative CREB mutant. The CFTR CRE will also drive cAMP-mediated expression when placed upstream of a heterologous basal promoter. These results demonstrate that CFTR is a bona fide CRE-dependent gene, and we suggest that CFTR expression levels in vivo may be responsive to hormones or drugs that activate the cAMP-dependent protein kinase system.

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