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J. Biol. Chem., Vol. 278, Issue 46, 45651-45660, November 14, 2003

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Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells^*

Manfred Kunz, Steffen Moeller¶, Dirk Koczan¶, Peter Lorenz¶, Roland H. Wenger||, Michael O. Glocker¶, Hans-Juergen Thiesen¶, Gerd Gross, and Saleh M. Ibrahim¶

From the Department of Dermatology and Venereology and ^¶Institute of Immunology and Proteome Center, University of Rostock, 18055 Rostock and the ^||Carl Ludwig Institute of Physiology, University of Leipzig, 04103 Leipzig, Germany

Hypoxia has a profound influence on progression and metastasis of malignant tumors. In the present report, we used the oligonucleotide microarray technique to identify new hypoxia-inducible genes in malignant melanoma with a special emphasis on angiogenesis factors. A commercially available Affymetrix® gene chip system was used to analyze five melanoma cell lines of different aggressiveness. A total of 160 hypoxia-inducible genes were identified, clustering in four different functional clusters. In search of putative angiogenesis and tumor progression factors within these clusters, Cyr61, a recently discovered angiogenesis factor, was identified. Cyr61 was hypoxia-inducible in low aggressive melanoma cells; however, it showed constitutive high expression in highly aggressive melanoma cells. Further analyses of transcriptional mechanisms underlying Cyr61 gene expression under hypoxia demonstrated that an AP-1 binding motif within the Cyr61 promoter plays a central role in the hypoxic regulation of Cyr61. It could be shown by use of in vitro luciferase assays, electrophoretic mobility shift assays, and immunoprecipitation that hypoxia-inducible factor-1 interacts with c-Jun/AP-1 and may thereby contribute to Cyr61 transcriptional regulation under hypoxia. Taken together, the presented data show that Cyr61 is a hypoxia-inducible angiogenesis factor in malignant melanoma with tumor stage-dependent expression. This may argue for a hypoxia-induced selection process during tumor progression toward melanoma cells with constitutive high Cyr61 expression.

Received for publication, February 7, 2003 , and in revised form, July 28, 2003.

^* This work was supported by German Bundesministerium für Bildung und Forschung Grant O31U214A (to M. K. and M. O. G.). 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.

To whom correspondence should be addressed: Dept. of Dermatology and Venereology, University of Rostock, Augusten Str. 80, 18055 Rostock, Germany. Tel.: 49-381-4949708; Fax: 49-381-4949702; E-mail: manfred.kunz{at}med.uni-rostock.de.

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