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J. Biol. Chem., Vol. 280, Issue 5, 3286-3294, February 4, 2005

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Loss of Net as Repressor Leads to Constitutive Increased c-fos Transcription in Cervical Cancer Cells^*

Jan van Riggelen, Gilles Buchwalter¶, Ubaldo Soto||, Johanna De-Castro Arce, Harald zur Hausen, Bohdan Wasylyk**, and Frank Rösl

From the Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany, the Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France, and the ^||Department of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, California 92350

We have investigated the expression of c-fos in cervical carcinoma cells and in somatic cell hybrids derived therefrom. In malignant cells, c-fos was constitutively expressed even after serum starvation. Dissection of the c-fos promoter showed that expression was mainly controlled by the SRE motif, which was active in malignant cells, but repressed in their non-malignant counterparts. Constitutive SRE activity was not mediated by sustained mitogen-activated protein kinase activity but because of inefficient expression of the ternary complex factor Net, which was either very low or even barely discernible. Chromatin immunoprecipitation assays revealed that Net directly binds to the SRE nucleoprotein complex in non-tumorigenic cells, but not in malignant segregants. Small interfering RNA targeted against Net resulted in enhanced c-fos transcription, clearly illustrating its repressor function. Conversely, stable ectopic expression of Net in malignant cells negatively regulated endogenous c-fos, resulting in a disappearance of the c-Fos protein from the AP-1 transcription complex. These data indicate that loss of Net and constitutive c-fos expression appear to be a key event in the transformation of cervical cancer cells.

Received for publication, August 30, 2004 , and in revised form, November 12, 2004.

^* 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.

^¶ Recipient of an Ministére de la Recherche et de la Technologie (MRT) fellowship.

^** Supported by the Association pour la Recherche sur le Cancer, the Ligue Nationale Française contre le Cancer (Equipe labelisée), the Ligue Régionale (Haut-et Bas-Rhin) contre le Cancer, the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, and the Hôpital Universitaire de Strasbourg.

To whom correspondence should be addressed: Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Tel.: 49-6221-424900; Fax: 49-6221-424902; E-mail: F.Roesl{at}dkfz.de.

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