Human Molecular Genetics, 2003, Vol. 12, No. 4 423-433
© 2003 Oxford University Press
Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation
1Institute of Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology and 2Department of Internal Medicine, Division of Endocrinology and Nephrology, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany, 3Max-Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany and 4Institute of Pharmacology, Toxicology and Natural Products, Department of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
Received November 17, 2002; Accepted December 14, 2002
The endothelin-converting enzyme (ECE)-1 gene is a candidate for human blood pressure (BP) regulation and we report the identification of the new gene variants T-839G, C-338A, L75F, A677V and C+295T. Transient transfection of the reporter constructs containing the -338A allele showed an increase in promoter activity compared with the wild-type promoter. EMSA revealed the specific binding of E2F-2 to both ECE-1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F-2 compared with -338C. The clinical relevance of this finding was analyzed in 704 hypertensive patients. In untreated hypertensive women, both the -338A and -839G alleles were significantly associated with ambulatory BP values. This study provides the first evidence of a link between the cell-cycle-associated E2F family and BP regulation via a component of the endothelin system.
* To whom correspondence should be addressed at: Department of Internal Medicine, Division of Endocrinology and Nephrology, Benjamin Franklin Medical Center, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. Tel: +49 3084453579; Fax: +49 3084454235; Email: ebrand{at}zedat.fu-berlin.de
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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