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Papers In Press, published online ahead of print September 11, 2002
J. Biol. Chem, 10.1074/jbc.M207160200
Submitted on July 17, 2002
Revised on August 23, 2002
Accepted on September 10, 2002
pathways
Immunology, Centro Investigaciones Biologicas, CSIC, Madrid 28040
Corresponding Author: bernabeu.c{at}cib.csic.es
Endoglin is a TGF-
co-receptor, mainly expressed on endothelial cells, and involved in cardiovascular development, angiogenesis and vascular remodeling. This is illustrated by the fact that mutations in endoglin gene give rise to the Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), a dominant vascular disease, whose clinical manifestations are originated by a mechanism of haploinsufficiency. Thus, studies on the regulated expression of endoglin are crucial to understand its function and to devise therapeutic strategies for HHT1. Endoglin is highly expressed in the neovasculature associated with hypoxia such as in ischemic tissues or tumours, but the molecular mechanism of this upregulation is unkown. Here, we have investigated the possible regulation of endoglin expression by hypoxia. Surface protein, transcript and promoter activity levels of endoglin were found to be upregulated by hypoxia, indicating that the regulation takes place at the transcriptional level. An hypoxia responsive element (HRE) downstream the main transcription start of the endoglin gene was functionally characterized. Whereas hypoxia alone moderately stimulated endoglin transcription, addition of TGF- under hypoxic conditions resulted in a transcriptional cooperation between both signaling pathways, leading to a marked stimulation of endoglin expression. Since endoglin basal transcription is sustained by Sp1, and TGF- and hypoxia signaling pathways are mediated by Smads and HIF-1, respectively, the involvement of these transcription factors was analyzed. Functional and co-immunoprecipitation experiments, demonstrated the existence of a multi-protein complex, Sp1-Smad3-HIF-1, on the endoglin promoter, mediating the cooperation between hypoxia and {TGF-beta} pathways. Within this multiprotein complex, Smad3 appears to function not only as a co-activator factor, but also as an adaptor between HIF-1 and Sp1, whose interaction is described. We propose that basal endoglin transcription (highly dependent on Sp1) may switch from a constitutive to an inducible state, through Sp1 interaction with HIF-1 and Smads transcription factors, induced by hypoxia and TGF-, respectively.
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