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An opposing view on WWOX protein function as a tumor suppressor
Akira Watanabe1, Yoshitaka Hippo, Hirokazu Taniguchi
1Genome Science Division and. Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Cancer Research
|December 26, 2003
Summary
WW domain-containing oxidoreductase (WWOX) protein levels are elevated in some cancers, not decreased. Truncated WWOX proteins are rapidly degraded, and WWOX shuttles between cytoplasm and nuclei in normal cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- WW domain-containing oxidoreductase (WWOX) is a candidate tumor suppressor gene implicated in cancer progression.
- Aberrant WWOX transcripts, rather than mutations, are suspected to influence cancer development.
- The precise role and expression patterns of endogenous WWOX protein in cancer remain largely uncharacterized.
Purpose of the Study:
- To characterize endogenous WW domain-containing oxidoreductase (WWOX) protein expression in normal and malignant cells.
- To investigate the stability and localization of WWOX protein.
- To re-evaluate the role of WWOX in cancer, particularly in gastric and breast carcinoma.
Main Methods:
- Generation and utilization of novel monoclonal antibodies for WWOX detection.
- Immunoblot analysis of WWOX protein expression across 49 cancer cell lines.
- Immunohistochemistry on cancer tissues and non-cancerous cells to determine WWOX localization and levels.
- Proteasomal degradation inhibition studies using MG-132.
Main Results:
- Endogenous WWOX protein was detected in its normal form in cancer cell lines, irrespective of aberrant RNA transcripts.
- Truncated WWOX proteins were identified upon proteasomal inhibition, suggesting rapid degradation.
- WWOX protein levels were elevated, not decreased, in gastric and breast carcinomas, challenging its classical tumor suppressor role.
- WWOX exhibited differential localization in normal epithelial cells (cytoplasm and nucleus) and showed dynamic nuclear-cytoplasmic shuttling in fibroblasts.
Conclusions:
- The study challenges the established view of WWOX as a classical tumor suppressor, showing elevated levels in certain carcinomas.
- Truncated WWOX forms are likely rapidly degraded by the proteasome.
- WWOX displays dynamic subcellular localization, shuttling between cytoplasm and nucleus, with distinct patterns in normal epithelial and cancerous cells.
- These findings offer new insights into WWOX function in both normal physiology and malignant transformation.