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J. Biol. Chem., Vol. 281, Issue 50, 38351-38357, December 15, 2006

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A Novel Role for Proline- and Acid-rich Basic Region Leucine Zipper (PAR bZIP) Proteins in the Transcriptional Regulation of a BH3-only Proapoptotic Gene^*

Adalberto Benito¹, Olga Gutierrez, Carlos Pipaon¹, Pedro J. Real², Frederic Gachon, Alistair E. Ritchie, and Jose L. Fernandez-Luna¹³

From the Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, 39008 Santander, Spain, and Department of Molecular Biology, University of Geneva, 1211 Geneve 4, Switzerland

Proline- and acid-rich (PAR) basic region leucine zipper (bZIP) proteins thyrotroph embryonic factor (TEF), D-site-binding protein (DBP), and hepatic leukemia factor have been involved in neurotransmitter homeostasis and amino acid metabolism. Here we demonstrate a novel role for these proteins in the transcriptional control of a BH3-only gene. PAR bZIP proteins are able to transactivate the promoter of bcl-gS. This promoter is particularly responsive to TEF activation and is silenced by NFIL3, a repressor that shares the consensus binding site with PAR bZIP proteins. Consistently, transfection of TEF induces the expression of endogenous bcl-gS in cancer cells, and this induction is independent of p53. A naturally occurring variant of DBP (tDBP), lacking the transactivation domain, has been identified and shown to impede the formation of active TEF dimers in a competitive manner and to reduce the TEF-dependent induction of bcl-gS. Of note, treatment of cancer cells with etoposide induces TEF activation and promotes the expression of bcl-gS. Furthermore, blockade of bcl-gS or TEF expression by a small interfering RNA strategy or transfection with tDBP significantly reduces the etoposide-mediated apoptotic cell death. These findings represent the first described role for PAR bZIP proteins in the regulation of a gene involved in the execution of apoptosis.

Received for publication, July 24, 2006 , and in revised form, September 19, 2006.

^* This work was supported by Fondo de Investigaciones Sanitarias grants PI040123 and RTICCC C03/10 (to J. L. F.-L.), and Grant 01/3037 (to A. 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.

¹ Both authors contributed equally to this work.

² Present address: Institute for Cancer Genetics, Columbia University, Irving Cancer Research Center 9-901B, New York, NY 10027-6902.

³ To whom correspondence should be addressed: Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, Edificio Escuela Universitaria de Enfermeria, Av. Valdecilla s/n, 39008 Santander, Spain. Tel.: 34-942-200952; Fax: 34-942-200952; E-mail: fluna{at}humv.es.

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