QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.005579v1 67/1/220    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liang, S.-H. Articles by Omiecinski, C. J. Search for Related Content PubMed PubMed Citation Articles by Liang, S.-H. Articles by Omiecinski, C. J.

Alternative Promoters Determine Tissue-Specific Expression Profiles of the Human Microsomal Epoxide Hydrolase Gene (EPHX1)

Center for Molecular Toxicology and Carcinogenesis, the Pennsylvania State University, University Park, Pennsylvania

Microsomal epoxide hydrolase (EPHX1) catalyzes hydration reactions that determine the cellular disposition of reactive epoxide derivatives. Whereas the previously defined EPHX1 exon 1 sequence (E1) is derived from a promoter proximal to exon 2 of the EPHX1 coding region, in this investigation, we identified an alternative EPHX1 exon 1 sequence, E1-b, originating from a gene promoter localized 18.5 kb upstream of exon 2. Northern hybridizations demonstrated that the E1-b variant is widely expressed and that the E1-b promoter functions as the primary driver of EPHX1 expression in human tissues. In contrast, the E1 promoter directs expression only in the liver. To examine the basis for liver-specific usage of the E1 promoter, we identified several potential cis-regulatory elements that included GATA (-110/-105) and hepatocyte nuclear factor 3 (HNF3) (-96/-88) motifs. GATA-4 was the principal GATA family member interacting with its respective motif, whereas both HNF3 and HNF3 were capable of interacting with the HNF3 element. GATA-4 and HNF3/HNF3 DNA binding complexes were enriched in hepatic cells. Site-directed mutagenesis and transactivation analyses of the E1 promoter revealed that GATA-4 is probably a principal factor that regulates liver-specific expression of the E1 variant, with HNF3 and HNF3 acting to negatively regulate GATA-4 function in hepatic cells.

Address correspondence to: Dr. Curtis Omiecinski, Center of Molecular Toxicology, 115 Henning, Pennsylvania State University, University Park, PA 16802. E-mail: cjo10{at}psu.edu

This article has been cited by other articles:

				S. Z. Abdel-Rahman, M. M. Ammenheuser, C. J. Omiecinski, J. K. Wickliffe, J. I. Rosenblatt, and J. B. Ward Jr. Variability in Human Sensitivity to 1,3-Butadiene: Influence of Polymorphisms in the 5'-Flanking Region of the Microsomal Epoxide Hydrolase Gene (EPHX1) Toxicol. Sci., May 1, 2005; 85(1): 624 - 631. [Abstract] [Full Text] [PDF]