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Physical Association with WWOX Suppresses c-Jun Transcriptional Activity

¹ Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio and ² Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia," Campus Germaneto, Catanzaro, Italy

Requests for reprints: Rami I. Aqeilan, Human Cancer Genetics, Ohio State University, Wiseman Hall, Room 456, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-3120; Fax: 614-292-3312; E-mail: rami.aqeilan{at}osumc.edu.

WWOX is a tumor suppressor that functions as a modular protein partner of transcription factors. WWOX contains two WW domains that mediate protein-protein interactions. In this report, we show that WWOX, via its first WW domain, specifically associates with the proline-rich motif of c-Jun proto-oncogene. Our data show that phosphorylation of c-Jun caused by overexpression of mitogen-activated protein kinase kinase kinase 1 (Mekk1), an upstream activator of c-Jun, enhances the interaction of c-Jun with WWOX. Furthermore, exposure of HaCaT keratinocytes to UVC radiation resulted in the association of endogenous WWOX and c-Jun. The WWOX-c-Jun complexes mainly occur in the cytoplasm. Expression of WWOX attenuates the ability of MEKK1 to increase the activity of a c-Jun-driven activating protein-1 (AP-1)-luciferase reporter plasmid. In contrast, a point mutation in the first WW domain of WWOX has no effect on transactivation of AP-1 when coexpressed with c-Jun protein. Our findings reveal a novel functional cross-talk between c-Jun transcription factor and WWOX tumor suppressor protein. (Cancer Res 2005; 66(24): 11585-9)

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