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J. Biol. Chem., Vol. 276, Issue 42, 38527-38535, October 19, 2001
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Pathways on Human Vascular Endothelial Growth Factor
Gene Expression*
§,,,,
From the Signaling by transforming growth factor (TGF)- Centro de Investigaciones Biológicas,
CSIC, Velázquez 144, 28006 Madrid, Spain and the
¶ Department of Anatomy and Cell Biology, University of
Toronto, Faculty of Medicine, Toronto, Ontario M5S 1A8, Canada
family members is mediated by Smad proteins that regulate gene
transcription through functional cooperativity and association with
other DNA-binding proteins. The hypoxia-inducible factor (HIF)-1 is a
transcriptional complex that plays a key role in oxygen-regulated gene
expression. We demonstrate that hypoxia and TGF- cooperate in the
induction of the promoter activity of vascular endothelial growth
factor (VEGF), which is a major stimulus in the promotion of
angiogenesis. This cooperation has been mapped on the human VEGF
promoter within a region at 
1006 to 954 that contains functional
DNA-binding sequences for HIF-1 and Smads. Optimal
HIF-1
-dependent induction of the VEGF promoter was
obtained in the presence of Smad3, suggesting an interaction between
these proteins. Consistent with this, co-immunoprecipitation experiments revealed that HIF-1 physically associates with Smad3. These results demonstrate that both TGF- and hypoxia signaling pathways can synergize in the regulation of VEGF gene expression at the
transcriptional level.
To whom correspondence should be addressed: Centro de
Investigaciones Biológicas, CSIC, Velázquez 144, Madrid
28006, Spain. Tel.: 34-91-5644562 (Ext. 4246); Fax: 34-91-5627518;
E-mail: bernabeu.c@ cib.csic.es.
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