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Updated: Aug 20, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor
Rami I Aqeilan1, Alexey Palamarchuk, Ronald J Weigel
1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
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.
Insights
The WWOX tumor suppressor protein interacts with the AP-2gamma transcription factor, inhibiting its oncogenic activity. WWOX sequesters AP-2gamma in the cytoplasm, suppressing its function in breast cancer.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The WWOX gene encodes a tumor suppressor protein, Wwox, which is altered in various cancers.
- Wwox protein contains WW domains involved in protein-protein interactions, including cross-talk with p73.
- AP-2gamma transcription factor is amplified in breast carcinoma.
Purpose of the Study:
- To investigate other interacting candidates for Wwox to further explore its biological function.
- To demonstrate a physical and functional association between the AP-2gamma transcription factor and the Wwox protein.
Main Methods:
- Investigated protein-protein interactions between Wwox and AP-2gamma.
- Utilized mutation analysis to assess the binding interaction between Wwox's WW domain and AP-2gamma's PPPY motif.
- Observed the effect of Wwox expression on the subcellular localization and function of AP-2gamma.
Main Results:
- Demonstrated a physical and functional association between Wwox and AP-2gamma.
- Showed that Wwox binds to the PPPY motif of AP-2gamma via its first WW domain.
- Found that Wwox expression causes nuclear AP-2gamma redistribution to the cytoplasm, suppressing its transactivating function.
Conclusions:
- Wwox tumor suppressor protein inhibits AP-2gamma oncogenic activity.
- Wwox suppresses AP-2gamma's function by sequestering it in the cytoplasm.
- This interaction suggests a novel mechanism for WWOX-mediated tumor suppression in breast cancer.
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