WW domain-containing oxidoreductase: a candidate tumor suppressor.

Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China.
Trends in Molecular Medicine (Impact Factor: 10.11). 02/2007; 13(1):12-22. DOI: 10.1016/j.molmed.2006.11.006
Source: PubMed

ABSTRACT Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others. Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown. We propose that suppression of WWOX expression by overexpressed hyaluronidases might contribute in part to the development of hormone independence in invasive cancer.

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    ABSTRACT: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-β, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/ Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration. INTRODUCTION Human and mouse WWOX/Wwox gene was first cloned in year 2000 [1-5; reviews]. Later on, the mouse Wwox genome, which has one million bases, was isolated [6]. WW domain-containing oxidoreductase (designated WWOX, FOR, or WOX1) is a candidate tumor suppressor. This 46-KDa protein has two N-terminal WW domains and one C-terminal SDR (short-chain alcohol dehydrogenase/ reductase), plus a nuclear localization signal located in between the WW domains. Human WWOX gene, encoding the WWOX protein, has been mapped to a fragile site on the chromosome ch16q23.3-24.1 [1-5; reviews]. WW domains have been shown to interact with a wide variety of signaling proteins and functioning as adaptor proteins, transcriptional co-activators, and probably ubiquitin ligases. The first WW domain of WWOX binds a broad spectrum of PPxY-containing proteins, including p63, p73, AP-2γ (Activator protein 2γ), ErbB4 (v-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4), Runx-2 (Runt-related transcription factor 2), Dvl-2 (Dishevelled homolog protein-2), SIMPLE (Small integral membrane protein of the lysosome/late endosome), MET (MET proto-oncogene), LMP2A (viral latent membrane protein 2A), and others [1-13]. In stark contrast, when WWOX becomes Tyr33-phosphorylated in the first WW domain, it acquires an enhanced binding capability with PPxY motif-deficient proteins such as p53, JNK1 (c-Jun N-terminal kinase 1), c-Jun (Jun proto-oncogene), CREB (cAMP responsive element binding protein), and Zfra (Zinc finger-like protein that regulates apoptosis) [4,8,10-14]. Additionally, the C-terminal SDR domain of WWOX physically interacts with membrane hyaluronidase Hyal-2 [15], tau [16] and GSK-3β (Glycogen synthase
    Oncotarget 12/2014; 5(23):11792. · 6.63 Impact Factor
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    ABSTRACT: Tamoxifen is a major treatment modality for estrogen receptor positive breast cancer, but the occurrence of resistance remains a problem. Recently, obesity-related leptin has been found to interfere with tamoxifen in breast cancer MCF-7 cells. In the present study we investigated the effect of leptin on three tamoxifen-treated breast cancer cell types (i.e., MDA-MB-231, MCF-7 and MCF-7/HER2). The effect of tamoxifen/leptin treatment was evaluated using a MTT cell viability assay. mRNA expression was assessed by real time PCR and protein expression by Western blotting. WWOX, Survivin and BCL2 gene promoter activities were evaluated by chromatin immunoprecipitation. Cell viability assays revealed that estrogen receptor negative MDA-MB-231 cells were resistant, that estrogen receptor positive MCF-7 cells were HER2 cells were relatively resistant to/HER2 cells were relatively resistant to tamoxifen, while leptin co-administration 'rescued' MCF-7 and, especially, MCF-7/HER2 cells from the anti-proliferative effect of tamoxifen. The cell lines also exhibited a different phosphorylation status of STAT3, a transcription factor that is activated by the obesity related leptin receptor b (Ob-Rb). Most importantly, chromatin immunoprecipitation assays revealed differential STAT3 binding to the anti-apoptotic BCL2 and pro-apoptotic WWOX gene promoters in MCF-7 and MCF-7/HER2 cells, leading to concomitant modifications of its mRNA/protein expression levels, thus providing a selective advantage to HER2 over-expressing MCF-7/HER2 cells after treatment with tamoxifen and tamoxifen plus leptin. Our study provides novel evidence indicating that synergy between the leptin/Ob-Rb/STAT3 signalling pathway and the HER2 receptor protects tamoxifen-treated HER2 over-expressing cells from the inhibitory effect of tamoxifen through differential regulation of apoptosis-related genes.
    Cellular Oncology 12/2014; DOI:10.1007/s13402-014-0213-5 · 2.12 Impact Factor
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    ABSTRACT: WW domain-containing oxidoreductase (WWOX) is a well-documented tumor suppressor protein that controls growth, survival, and metastasis of malignant cells. To counteract WWOX's suppressive effects, cancer cells have developed many strategies either to downregulate WWOX expression or to functionally inactivate WWOX. Relatively unknown is, in the context of those cancers associated with certain viruses or bacteria, how the oncogenic pathogens deal with WWOX. Here we review recent studies showing different strategies utilized by three cancer-associated pathogens. Helicobactor pylori reduces WWOX expression through promoter hypermethylation, an epigenetic mechanism also occurring in many other cancer cells. WWOX has a potential to block canonical NF-κB activation and tumorigenesis induced by Tax, an oncoprotein of human T-cell leukemia virus. Tax successfully overcomes the blockage by inhibiting WWOX expression through activation of the non-canonical NF-κB pathway. On the other hand, latent membrane protein 2A of Epstein-Barr virus physically interacts with WWOX and redirects its function to trigger a signaling pathway that upregulates matrix metalloproteinase 9 and cancer cell invasion. These reports may be just "the tip of the iceberg" regarding multiple interactions between WWOX and oncogenic microbes. Further studies in this direction should expand our understanding of infection-driven oncogenesis. © 2014 by the Society for Experimental Biology and Medicine.
    Experimental Biology and Medicine 12/2014; DOI:10.1177/1535370214561957 · 2.23 Impact Factor


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