Physical association with WWOX suppresses c-Jun transcriptional activity.
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.
Gaudio
Eugenio
E
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Palamarchuk
Alexey
A
Palumbo
Tiziana
T
Trapasso
Francesco
F
Pekarsky
Yuri
Y
Croce
Carlo M
CM
Aqeilan
Rami I
RI
D002460:Cell Line; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016758:Genes, jun; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D000090063:Proto-Oncogene Mas; D013489:Suppression, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human