Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2γ transcription factor

Rami I. Aqeilan, Alexey Palamarchuk, Ronald J. Weigel, Juan J. Herrero, Yuri Pekarsky, Carlo M. Croce*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


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

Original languageAmerican English
Pages (from-to)8256-8261
Number of pages6
JournalCancer Research
Issue number22
StatePublished - 15 Nov 2004
Externally publishedYes

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