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Papers In Press, published online ahead of print September 4, 2002
INSERM, INSERM U 465, Paris 75006
Corresponding Author: mguerre{at}bhdc.jussieu.fr
Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1a / HIF-1b complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1a expression vector. Exogenous HIF-1a markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1b was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1a. These data suggest that HIF-1a / HIF-1b dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1a producing transcriptionally inactive HIF-1b / HIF-1a dimers. This mutant HIF-1a protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1a. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning -120 to -116 bp relative to start site, was required for CoCl2 and exogenous HIF-1a induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro translated HIF-1a and HIF-1b proteins, demonstrated binding to this HRE and not to mutated sequences, only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at -116 in the proximal promoter.
J. Biol. Chem, 10.1074/jbc.M206775200
Submitted on July 8, 2002
Revised on August 27, 2002
Accepted on September 4, 2002
Hypoxia-inducible factor 1 (HIF-1) transactivates the human leptin gene promoter
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