HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 6, 3365-3375, February 8, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/6/3365    most recent M708241200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anelli, V. Articles by Obeid, L. M. Search for Related Content PubMed PubMed Citation Articles by Anelli, V. Articles by Obeid, L. M. Social Bookmarking                      What's this?

Sphingosine Kinase 1 Is Up-regulated during Hypoxia in U87MG Glioma Cells

ROLE OF HYPOXIA-INDUCIBLE FACTORS 1 AND 2^*

Viviana Anelli, Christopher R. Gault^¶, Amy B. Cheng, and Lina M. Obeid^¶||1

From the ^||Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401, the Departments of ^¶Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29403, and the Department of Medical Chemistry, Biochemistry, and Biotechnology, University of Milan, Segrate, Milan 20090, Italy

Sphingosine 1-phosphate (S1P), a sphingolipid metabolite that plays an important role in the regulation of cell survival, growth, migration, and angiogenesis, acts both inside the cells and as an extracellular mediator through binding to five G protein-coupled receptors (S1P_1-5). Sphingosine kinase 1 (SK1), the enzyme responsible for S1P production, is overexpressed in many solid tumors, including gliomas. One common feature of these tumors is the presence of "hypoxic regions," characterized by cells expressing high levels of hypoxia-inducible factors HIF-1 and HIF-2, two transcription regulators that modulate the levels of proteins with crucial roles in tumor progression. So far, nothing is known about the role and the regulation of SK1 during tumor-induced hypoxia or about SK1 regulation and HIFs. Here we investigated the role of HIF-1 and HIF-2 in the regulation of SK1 during hypoxic stress in glioma-derived U87MG cells. We report that hypoxia increases SK1 mRNA levels, protein expression, and enzyme activity, followed by intracellular S1P production and S1P release. Interestingly, knockdown of HIF-2 by small interfering RNA abolished the induction of SK1 and the production of extracellular S1P after CoCl₂ treatment, whereas HIF-1 small interfering RNA resulted in an increase of HIF-2 and of SK1 protein levels. Moreover, using chromatin immunoprecipitation analysis, we demonstrate that HIF-2 binds the SK1 promoter. Functionally, we demonstrate that conditioned medium from hypoxia-treated tumor cells results in neoangiogenesis in human umbilical vein endothelial cells in a S1P receptor-dependent manner. These studies provide evidence of a link between S1P production as a potent angiogenic agent and the hypoxic phenotype observed in many tumors.

Received for publication, October 3, 2007 , and in revised form, November 30, 2007.

^* This work was supported in part by NCI, National Institutes of Health (NIH), Grant P01 CA097132, NIGMS, NIH, Grant R01 GM062887, and a MERIT Award (to L. M. O.) from the Office of Research and Development, Department of Veterans Affairs, Ralph H. Johnson Veterans Affairs Medical Center (Charleston, SC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Medical University of South Carolina, Dept. of Medicine, Division of General Internal Medicine/Geriatrics, P.O. Box 250779, Charleston, SC 29403. Tel.: 843-876-5169; Fax: 843-876-5172; E-mail: obeid{at}musc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Ader, B. Malavaud, and O. Cuvillier When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy Cancer Res., May 1, 2009; 69(9): 3723 - 3726. [Abstract] [Full Text] [PDF]

				J. S. Karliner Sphingosine kinase regulation and cardioprotection Cardiovasc Res, May 1, 2009; 82(2): 184 - 192. [Abstract] [Full Text] [PDF]

				S. E. Schnitzer, A. Weigert, J. Zhou, and B. Brune Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells Mol. Cancer Res., March 1, 2009; 7(3): 393 - 401. [Abstract] [Full Text] [PDF]

				I. Ader, L. Brizuela, P. Bouquerel, B. Malavaud, and O. Cuvillier Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1{alpha} during Hypoxia in Human Cancer Cells Cancer Res., October 15, 2008; 68(20): 8635 - 8642. [Abstract] [Full Text] [PDF]