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J. Biol. Chem., Vol. 279, Issue 8, 6737-6745, February 20, 2004

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bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation

INVOLVEMENT OF ERK1/ERK2 ACTIVITY^*

Daniela Trisciuoglio¶, Angela Iervolino¶, Antonio Candiloro, Gabriella Fibbi||, Maurizio Fanciulli**, Uwe Zangemeister-Wittke, Gabriella Zupi, and Donatella Del Bufalo

From the Experimental Chemotherapy Laboratory and ^**Laboratory B, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy, the ^||Department of Pathology and Oncology, University of Florence, 50134 Florence, Italy, and the Department of Oncology, University Hospital Zurich, Zurich 8044, Switzerland

We have previously demonstrated that Bcl-2 overexpression in human breast carcinoma and melanoma cells synergizes with hypoxia to increase angiogenesis through up-regulation of vascular endothelial growth factor. In this work we demonstrated, for the first time, that Bcl-2 overexpression in cancer cells exposed to hypoxia modulates urokinase plasminogen activator receptor (uPAR) expression through Sp1 transcription factor and that the extracellular signal-regulated kinase (ERK) pathway plays a role in Sp1 transcriptional activity. In particular, an increase in uPAR protein and mRNA expression was found in melanoma bcl-2 transfectants grown under hypoxia when compared with control cells, and a decrease of uPAR protein expression was induced by treatment of cells with specific bcl-2 antisense oligonucleotides. Up-regulation of uPAR expression was accompanied by increased Sp1 protein expression, stability, serine phosphorylation, and DNA binding activity. Treatment of cells with mitramycin A, an inhibitor of Sp1 activity, confirmed the role of Sp1 transcriptional activity in uPAR induction by Bcl-2. The contribution of the ERK pathway in Sp1-increased transcriptional activity was demonstrated by the use of chemical inhibition. In fact, ERK kinase activation was induced in Bcl-2-overexpressing cells exposed to hypoxia, and the ERK kinase inhibitor UO126 was able to down-regulate Sp1 phosphorylation and DNA binding activity. Using a human breast carcinoma line, we obtained data supporting our findings with melanoma cells and identified a link between the induction of Sp1 and uPAR expression as a common bcl-2-controlled phenomenon in human tumors. In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway.

Received for publication, August 13, 2003 , and in revised form, October 14, 2003.

^* This work was supported by grants from the Ministero della Sanità (to D. D. B.) and Italian Association for Cancer Research (to D. D. B.). 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.

Recipients of a fellowship from the Italian Foundation for Cancer Research (FIRC).

^¶ These authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 39-06-52662537; Fax: 39-06-52662505; E-mail: delbufalo{at}ifo.it.

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