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J. Biol. Chem., Vol. 281, Issue 16, 11279-11291, April 21, 2006

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Functional Genomic Responses to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTR⁵⁰⁸ in the Lung^*

Yan Xu¹, Cong Liu^¶, Jean C. Clark, and Jeffrey A. Whitsett

From the Divisions of Pulmonary Biology, Biomedical Informatics, and ^¶Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039

Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and 508-CFTR were assessed in transgenic mice that 1) lack CFTR expression (Cftr^-/-); 2) express the human 508 CFTR (CFTR⁵⁰⁸); 3) overexpress the normal human CFTR (CFTR^tg) in respiratory epithelial cells. Genes were selected from Affymetrix Murine Gene-Chips analysis and subjected to functional classification, k-means clustering, promoter cis-elements/modules searching, literature mining, and pathway exploring. Genomic responses to Cftr^-/- were not corrected by expression of CFTR ⁵⁰⁸. Genes regulating host defense, inflammation, fluid and electrolyte transport were similarly altered in Cftr^-/- and CFTR ⁵⁰⁸ mice.CFTR⁵⁰⁸ induced a primary disturbance in expression of genes regulating redox and antioxidant systems. Genomic responses to CFTR^tg were modest and were not associated with lung pathology. CFTR^tg and CFTR⁵⁰⁸ induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum-associated degradation pathway. RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within a multiprotein complex whose members interact at the level of protein-protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF.

Received for publication, November 9, 2005 , and in revised form, January 3, 2006.

^* This work was supported by the National Cystic Fibrosis Foundation, Research and Development Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3 and Tables SI-SIV.

¹ To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-8921; Fax: 513-636-7868; E-mail: yan.xu{at}cchmc.org.

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