Journal Article

Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region

Rosa Di Bitondo, Adrian J. Hall, Ian R. Peake, Licia Iacoviello and Peter R. Winship

in Human Molecular Genetics

Volume 11, issue 7, pages 723-731
Published in print April 2002 | ISSN: 0964-6906
Published online April 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.7.723
Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region

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Reporter gene analysis of two regions of the human factor VII (FVII) gene promoter (residues –658 to –1 and –348 to –1, where +1 is the start site of translation) in the mammalian liver-derived cell line HepG2 showed reduced transcriptional activity in the presence of oestrogenic factors. This effect was independent of promoter polymorphic haplotype. Similar analysis using a smaller region of the promoter spanning residues –187 to –1 failed to show any evidence of oestrogenic suppression. Electrophoretic mobility shift assays and supershift assays using recombinant oestrogen receptor α and anti-oestrogen receptor antibody localized the sequence motif to which oestrogen receptor was binding to residues –225 to –212 of the FVII promoter. The lack of oestrogenic suppression in a reporter gene construct spanning residues –658 to –1 modified to abolish oestrogen receptor binding at this site, confirmed the functional significance of this motif. Although superficially similar to the classical oestrogen response element (ORE), comprising two half sites separated by three spacer nucleotides, the FVII ORE represents an alternative type of ORE in which the two half sites are separated by just two spacer nucleotides. EMSAs indicated that increasing spacer nucleotide number from two to three in the FVII ORE, or decreasing it from three to two in a consensus ORE sequence motif, had a small effect on the binding affinity for oestrogen receptor. These data correlate with and provide a plausible mechanism for the inverse relationship between FVII and oestradiol levels observed during the menstrual cycle.

Journal Article.  6908 words.  Illustrated.

Subjects: Genetics and Genomics

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