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Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways

Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways
Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways
Endoglin is a transforming growth factor-beta (TGF-beta) co-receptor expressed mainly on endothelial cells and involved in cardiovascular development, angiogenesis, and vascular remodeling. This is illustrated by the fact that mutations in the endoglin gene give rise to hereditary hemorrhagic telangiectasia type 1, a dominant vascular disease with clinical manifestations that originate by a mechanism of haploinsufficiency. Thus, studies on the regulated expression of endoglin are crucial to devising therapeutic strategies for hereditary hemorrhagic telangiectasia type 1. Endoglin is highly expressed in the neovasculature associated with hypoxia such as ischemic tissues and tumors, but the molecular mechanism of this up-regulation is unknown. 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 up-regulated by hypoxia, indicating that the regulation takes place at the transcriptional level. A hypoxia-responsive element downstream of the main transcription start site of the endoglin gene was functionally characterized. Whereas hypoxia alone moderately stimulated endoglin transcription, addition of TGF-beta under hypoxic conditions resulted in transcriptional cooperation between both signaling pathways, leading to marked stimulation of endoglin expression. Because basal endoglin transcription is sustained by Sp1, and TGF-beta and hypoxia signaling pathways are mediated by Smad proteins and hypoxia-inducible factor-1 (HIF-1), respectively, the involvement of these transcription factors was analyzed. Functional and co-immunoprecipitation experiments demonstrated the existence of a multiprotein complex (Sp1.Smad3.HIF-1) on the endoglin promoter, mediating the cooperation between the hypoxia and TGF-beta pathways. Within this multiprotein complex, Smad3 appears to function not only as a coactivator factor, but also as an adaptor between HIF-1 and Sp1. 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 Smad transcription factors, induced by hypoxia and TGF-beta, respectively.
0021-9258
43799-43808
Sánchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Botella, Luisa M.
33922361-7216-4770-8b71-fc2369e7df06
Velasco, Beatriz
c8fc68a3-8b68-4306-adcc-979b4243fa0c
Langa, Carmen
0de1f831-149d-42f6-b792-cb66d3d6b6e9
Bernabéu, Carmelo
30da3b6d-c832-4d23-8ea8-79e4c808ca05
Sánchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Botella, Luisa M.
33922361-7216-4770-8b71-fc2369e7df06
Velasco, Beatriz
c8fc68a3-8b68-4306-adcc-979b4243fa0c
Langa, Carmen
0de1f831-149d-42f6-b792-cb66d3d6b6e9
Bernabéu, Carmelo
30da3b6d-c832-4d23-8ea8-79e4c808ca05

Sánchez-Elsner, Tilman, Botella, Luisa M., Velasco, Beatriz, Langa, Carmen and Bernabéu, Carmelo (2002) Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. The Journal of Biological Chemistry, 277 (46), 43799-43808. (doi:10.1074/jbc.M207160200).

Record type: Article

Abstract

Endoglin is a transforming growth factor-beta (TGF-beta) co-receptor expressed mainly on endothelial cells and involved in cardiovascular development, angiogenesis, and vascular remodeling. This is illustrated by the fact that mutations in the endoglin gene give rise to hereditary hemorrhagic telangiectasia type 1, a dominant vascular disease with clinical manifestations that originate by a mechanism of haploinsufficiency. Thus, studies on the regulated expression of endoglin are crucial to devising therapeutic strategies for hereditary hemorrhagic telangiectasia type 1. Endoglin is highly expressed in the neovasculature associated with hypoxia such as ischemic tissues and tumors, but the molecular mechanism of this up-regulation is unknown. 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 up-regulated by hypoxia, indicating that the regulation takes place at the transcriptional level. A hypoxia-responsive element downstream of the main transcription start site of the endoglin gene was functionally characterized. Whereas hypoxia alone moderately stimulated endoglin transcription, addition of TGF-beta under hypoxic conditions resulted in transcriptional cooperation between both signaling pathways, leading to marked stimulation of endoglin expression. Because basal endoglin transcription is sustained by Sp1, and TGF-beta and hypoxia signaling pathways are mediated by Smad proteins and hypoxia-inducible factor-1 (HIF-1), respectively, the involvement of these transcription factors was analyzed. Functional and co-immunoprecipitation experiments demonstrated the existence of a multiprotein complex (Sp1.Smad3.HIF-1) on the endoglin promoter, mediating the cooperation between the hypoxia and TGF-beta pathways. Within this multiprotein complex, Smad3 appears to function not only as a coactivator factor, but also as an adaptor between HIF-1 and Sp1. 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 Smad transcription factors, induced by hypoxia and TGF-beta, respectively.

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Published date: November 2002

Identifiers

Local EPrints ID: 47980
URI: http://eprints.soton.ac.uk/id/eprint/47980
ISSN: 0021-9258
PURE UUID: ebdcb45d-0d6f-4582-b759-fd90eb605b5b
ORCID for Tilman Sánchez-Elsner: ORCID iD orcid.org/0000-0003-1915-2410

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Date deposited: 16 Aug 2007
Last modified: 16 Mar 2024 03:56

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Contributors

Author: Luisa M. Botella
Author: Beatriz Velasco
Author: Carmen Langa
Author: Carmelo Bernabéu

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