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Originally published In Press as doi:10.1074/jbc.M300319200 on February 21, 2003

J. Biol. Chem., Vol. 278, Issue 18, 15473-15483, May 2, 2003
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Characterization of the Human Lung CYP2F1 Gene and Identification of a Novel Lung-specific Binding Motif*

Brian A. CarrDagger , Jie WanDagger , Ronald N. Hines§, and Garold S. YostDagger

From the Dagger  Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and § Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-4801

The CYP2F1 gene encodes a cytochrome P450 enzyme capable of bioactivating a number of pulmonary-selective toxicants. The expression of CYP2F1 is highly tissue-selective; the highest expression is observed in the lung with little or no hepatic expression. The objective of these studies was to elucidate the mechanisms that govern the unique tissue-specific regulation of CYP2F1. Cosmid and bacterial artificial chromosome clones were screened and sequenced to identify a gene that spanned 14 kbp containing 10 exons, including an untranslated exon 1. Primer extension analysis and 5'-rapid amplification of cDNA ends were used to identify the transcription start site. Several sequences homologous to known cis-elements were identified in the 5'-upstream region of the CYP2F1 promoter. Transient transfection studies with luciferase reporter constructs demonstrated a significant functional lung cell-specific CYP2F1 promoter region (from position -129 to +115). DNase footprinting analysis of 1.6 kbp of the upstream sequence with nuclear extracts from human lung tissues revealed one strong DNA-protein complex at -152 to -182. This nuclear protein (called lung-specific factor, LSF) was present only in lung but not liver or heart tissues. Competitive electrophoretic mobility shift assays characterized a DNA consensus site, within the LSF-binding domain, that was highly similar to two E box motifs, but no known "E box" trans-factors were identified. These studies identified a novel LSF and its consensus sequence that may control tissue-specific expression of CYP2F1.

* This work was supported by NHLBI Grant HL60143 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) NM_000774.

To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, 30 S. 2000 E., Rm. 201, University of Utah, Salt Lake City, UT 84112. Tel.: 801-581-7956; Fax: 801-585-3945; E-mail: gyost@pharm.utah.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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