Abstract:
:Tyrosine kinase cascades may play a role in the hypoxic regulation of hypoxia-inducible factor (HIF)-1. We investigated the role of tyrosine kinase phosphorylation and of the Shc/Ras cascade on hypoxic HIF-1 stabilization. Exposure of human umbilical vein endothelial cells to hypoxia results in HIF protein stabilization as early as 10 minutes, with a maximum at 3 hours, and also in Shc tyrosine phosphorylation, with a maximum at 10 minutes. To test whether Shc directly mediates hypoxia-induced HIF stabilization, human umbilical vein endothelial cells were transfected with a dominant-negative Shc mutant (dnShc), resulting in significantly reduced HIF protein levels compared with control. Similar results were obtained with cells transfected with dominant-negative Ras, a known downstream effector of Shc. Hypoxia-induced Ras activity was significantly reduced in cells transfected with dnShc compared with control levels, indicating that Ras indeed acts downstream from Shc. Moreover, cells pretreated with a specific Raf-1 kinase inhibitor, a known downstream effector of Ras, exhibited reduced HIF protein levels. To examine the functional consequences of Shc in hypoxic signaling, HIF-1 ubiquitination, protein stabilization, and endothelial cell migration were assessed. Overexpression of dnShc increased ubiquitination of HIF-1 and reduced the half-life of the protein. Moreover, dnShc, dominant-negative Ras, or the Raf-1 kinase inhibitor significantly inhibited migration under hypoxia. Thus, Shc in concert with Ras and Raf-1 contributes to hypoxia-induced HIF-1alpha protein stabilization and endothelial cell migration.
journal_name
Circ Resjournal_title
Circulation researchauthors
Jung F,Haendeler J,Hoffmann J,Reissner A,Dernbach E,Zeiher AM,Dimmeler Sdoi
10.1161/01.res.0000024412.24491.casubject
Has Abstractpub_date
2002-07-12 00:00:00pages
38-45issue
1eissn
0009-7330issn
1524-4571journal_volume
91pub_type
杂志文章abstract::In the present study, we established an injury model of the mouse carotid artery. Complete removal of the endothelium was achieved with a flexible wire. A platelet monolayer covered the denuded surface, and damage to underlying medial smooth muscle cells (SMCs) was detected. Injection of [3H]thymidine was used to dete...
journal_title:Circulation research
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更新日期:2007-03-16 00:00:00
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更新日期:1991-12-01 00:00:00
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更新日期:1995-08-01 00:00:00
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更新日期:1984-12-01 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:2014-01-17 00:00:00
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pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.307017
更新日期:2016-01-22 00:00:00
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doi:10.1161/01.res.67.6.1510
更新日期:1990-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:1990-06-01 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1977-05-01 00:00:00
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更新日期:1983-08-01 00:00:00
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更新日期:2009-04-10 00:00:00
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更新日期:2017-12-08 00:00:00
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更新日期:1982-11-01 00:00:00
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更新日期:1992-10-01 00:00:00
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更新日期:2008-06-06 00:00:00
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更新日期:1977-11-01 00:00:00
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更新日期:2017-09-29 00:00:00
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pub_type: 杂志文章
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更新日期:2004-12-10 00:00:00