Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells

Schwalm, Stephanie; Döll, Frauke; Römer, Isolde; Bubnova, Svetlana; Pfeilschifter, Josef; Huwiler, Andrea (2008). Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells. Biochemical and biophysical research communications, 368(4), pp. 1020-5. Orlando, Fla.: Academic Press 10.1016/j.bbrc.2008.01.132

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Sphingosine kinases (SK) catalyze the production of sphingosine-1-phosphate which in turn regulates cell responses such as proliferation and migration. Here, we show that exposure of the human endothelial cell line EA.hy 926 to hypoxia stimulates a increased SK-1, but not SK-2, mRNA, protein expression, and activity. This effect was due to stimulated SK-1 promoter activity which contains two putative hypoxia-inducible factor-responsive-elements (HRE). By deletion of one of the two HREs, hypoxia-induced promoter activation was abrogated. Furthermore, hypoxia upregulated the expression of HIF-1alpha and HIF-2alpha, and both contributed to SK-1 gene transcription as shown by selective depletion of HIF-1alpha or HIF-2alpha by siRNA. The hypoxia-stimulated SK-1 upregulation was functionally coupled to increased migration since the selective depletion of SK-1, but not of SK-2, by siRNAs abolished the migratory response. In summary, these data show that hypoxia upregulates SK-1 activity and results in an accelerated migratory capacity of endothelial cells. SK-1 may thus serve as an attractive therapeutic target to treat diseases associated with increased endothelial migration and angiogenesis such as cancer growth and progression.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

ISSN:

0006-291X

ISBN:

18261991

Publisher:

Academic Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:03

Last Modified:

04 May 2014 23:19

Publisher DOI:

10.1016/j.bbrc.2008.01.132

PubMed ID:

18261991

Web of Science ID:

000254106700031

URI:

https://boris.unibe.ch/id/eprint/27523 (FactScience: 108722)

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