Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor.
The WWOX gene encodes a tumor suppressor WW domain-containing protein, Wwox. Alterations of WWOX have been demonstrated in multiple types of cancer, and introduction of Wwox into Wwox-negative tumor cells has resulted in tumor suppression and apoptosis. The Wwox protein contains two WW domains that typically bind proline-rich motifs and mediate protein-protein interactions. Recently, we have described functional cross-talk between the Wwox protein and the p53 homologue, p73. To further explore the biological function of Wwox, we investigated other interacting candidates. In this report, we demonstrate a physical and functional association between AP-2gamma transcription factor and the Wwox protein. AP-2gamma at 20q13.2 encodes a transcription factor and is frequently amplified in breast carcinoma. We show that Wwox binds to the PPPY motif of AP-2gamma via its first WW domain. Alterations of tyrosine 33 in the first WW domain of Wwox or the proline-rich motif in AP-2gamma dramatically reduce this interaction. In addition, our results demonstrate that Wwox expression triggers redistribution of nuclear AP-2gamma to the cytoplasm, hence suppressing its transactivating function. Our results suggest that Wwox tumor suppressor protein inhibits AP-2gamma oncogenic activity by sequestering it in the cytoplasm.
Aqeilan
Rami I
RI
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Palamarchuk
Alexey
A
Weigel
Ronald J
RJ
Herrero
Juan J
JJ
Pekarsky
Yuri
Y
Croce
Carlo M
CM
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism*; D011485:Protein Binding; D013347:Subcellular Fractions / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
D017931:DNA Primers; D004268:DNA-Binding Proteins; C493679:TFAP2C protein, human; C583890:Tfap2c protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human