CCAAT/Enhancer-binding Protein-β Participates in Insulin-responsive Expression of the Factor VII Gene*
- ‡Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132 and §Harvard Medical School, Boston, Massachusetts 02115
- 1 To whom correspondence should be addressed: Veterans Affairs Boston Healthcare System (151), 1400 VFW Pkwy., West Roxbury, MA 02132. Tel.: 857-203-5141; Fax: 857-203-5596; E-mail: josephine_carew{at}hms.harvard.edu.
Abstract
Expression of the human coagulation factor VII (FVII) gene by hepatoma cells was modulated in concert with levels of glucose and insulin in the culture medium. In low glucose medium without insulin, amounts of both FVII mRNA and secreted FVII protein were coordinately increased; in the presence of glucose with insulin, both were decreased. Analysis of the FVII promoter showed that these effects could be reproduced in a reporter-gene system, and a small promoter element immediately upstream of the translation start site of the gene, which mediated these effects, was identified. Mutation of this element largely abrogated the glucose/insulin-responsive change in expression of the reporter gene. Several members of the CCAAT/enhancer-binding protein family were found to be capable of binding the identified sequence element but not the mutated element. The expression of a FVII minigene directed by a segment of the native FVII promoter responded to co-expressed activating and inhibiting forms of CCAAT/enhancer-binding protein β.
Footnotes
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↵2 The abbreviations used are: FVII, coagulation factor VII; FVII:Ag, factor VII antigen; C/EBP, CCAAT/enhancer-binding protein; LAP, liver-activating protein; LIP, liver-inhibiting protein; EMSA, electrophoretic mobility shift assay; HNF4, hepatic nuclear factor 4; AARE, amino acid response element; NSRE, nutrient-sensing response element; AS, asparagine synthase; SNAT2, sodium-coupled neutral amino acid transport; CHOP, C/EBP-homologous protein; hGH, human growth hormone; CHO, Chinese hamster ovary; UTR, untranslated region.
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↵* This work was supported by a Department of Veterans Affairs Merit Research Service Award (to J. A. C.). 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.
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- Received June 7, 2007.
- Revision received July 25, 2007.
