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[Cancer Research 64, 8256-8261, November 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Physical and Functional Interactions between the Wwox Tumor Suppressor Protein and the AP-2{gamma} Transcription Factor

Rami I. Aqeilan1, Alexey Palamarchuk1, Ronald J. Weigel2, Juan J. Herrero3, Yuri Pekarsky1 and Carlo M. Croce1

1 Kimmel Cancer Center and 2 Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and 3 AxCell Biosciences Corporation, Newtown, Pennsylvania

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-2{gamma} transcription factor and the Wwox protein. AP-2{gamma} 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-2{gamma} via its first WW domain. Alterations of tyrosine 33 in the first WW domain of Wwox or the proline-rich motif in AP-2{gamma} dramatically reduce this interaction. In addition, our results demonstrate that Wwox expression triggers redistribution of nuclear AP-2{gamma} to the cytoplasm, hence suppressing its transactivating function. Our results suggest that Wwox tumor suppressor protein inhibits AP-2{gamma} oncogenic activity by sequestering it in the cytoplasm.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2004 by the American Association for Cancer Research.