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J. Biol. Chem., Vol. 280, Issue 36, 31809-31817, September 9, 2005

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Fibromodulin Gene Transcription Is Induced by Ultraviolet Irradiation, and Its Regulation Is Impaired in Senescent Human Fibroblasts^*

Maria Assunta Bevilacqua, Barbara Iovine, Nicola Zambrano, Chiara D'Ambrosio, Andrea Scaloni, Tommaso Russo¶, and Filiberto Cimino||

From the Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, CEINGE Biotecnologie avanzate, 80131 Napoli, Italy and Proteomics and Mass Spectrometry Laboratory, ISPAAM, Consiglio Nazionale delle Ricerche, 80147 Naples, Italy

Cells undergoing replicative senescence display an altered pattern of gene expression. Senescent fibroblasts show significant changes in the expression of mRNAs encoding extracellular matrix-remodeling proteins; among these mRNAs, the mRNA encoding fibromodulin is highly decreased in these cells. To understand the molecular basis of this phenomenon, we explored the regulatory mechanisms of the human fibromodulin gene. We found that fibromodulin gene promoter contains a cis-element, crucial for its basal expression, that forms a DNA-protein complex when exposed to nuclear extracts from exponentially growing human fibroblasts and not to extracts from cells undergoing senescence by repeated in vitro passages or by mild oxidative stress. The purification of this complex showed that it contains the damage-specific DNA-binding protein DDB-1. The latter is known to be induced by UV irradiation; therefore we checked whether fibromodulin gene promoter is regulated upon the exposure of the cells to UV rays. The results showed that, in exponentially growing fibroblasts, the promoter efficiency is increased by UV irradiation and the DDB-1-containing complex is robustly enriched in cells exposed to UV light. Accordingly, in these experimental conditions the endogenous fibromodulin mRNA accumulates to very high levels. On the contrary, senescent cells did not show any activation of the fibromodulin gene promoter, any induction of the DDB-1-containing complex, or any accumulation of fibromodulin mRNA. These phenomena are accompanied in senescent cells by a decrease of the UV-damaged DNA binding activity.

Received for publication, December 30, 2004 , and in revised form, July 1, 2005.

^* This work was supported by MIUR-PRIN (to F. C.), FIRB2001 RBAU01PRLA-002 to (A. S.), by the NOGEC Oncogenomic Centre at CEINGE supported by Associazione Italiana Ricerca sul Cancro, VI FP of EC Grant LSHM-CT-2003-503330, and FIRB-Proneuro (to T. R.). 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.jbs.org) contains supplemental material.

¶ To whom correspondence may be addressed: CEINGE Biotecnologie avanzate, via Comunale Margherita 482, 80145 Napoli, Italy. Tel.: 390813722863; Fax: 390813722808; E-mail: russot{at}dbbm.unina.it. || To whom correspondence may be addressed: Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, via S. Pansini 5, 80131 Napoli, Italy. E-mail: cimino{at}dbbm.unina.it.

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