WW domain-containing oxidoreductase: A candidate tumor suppressor

Department of Microbiology and Immunology, National Cheng Kung University, 臺南市, Taiwan, Taiwan
Trends in Molecular Medicine (Impact Factor: 9.45). 02/2007; 13(1):12-22. DOI: 10.1016/j.molmed.2006.11.006
Source: PubMed


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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Available from: Nan-Shan Chang
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    • "The first N-terminal WW domain is needed for the classical WW-PPXY interaction. The proteins with the SDR domain are involved in oxidation and reduction of various substrates such as lipid hormones, sugars, alcohols and retinoids 6. "
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    ABSTRACT: WWOX, a gene that spans the second most common chromosomal fragile site (FRA16D), often exhibits homozygous deletions and translocation breakpoints under multiple cellular stresses induced by extrinsic or intrinsic factors, such as hypoxia, UV, and DNA damage regents. Loss of WWOX is closely related to genomic instability, tumorigenesis, cancer progression and therapy resistance. WWOX heterozygous knockout mice show an increased incidence of spontaneous or induced tumors. WWOX can interact via the WW domain with proteins that possess proline PPxY motifs and is involved in a variety of cellular processes. Accumulating evidence has shown that WWOX that contains a short-chain dehydrogenase/reductase (SDR) domain is involved in steroid metabolism and bone development. Reduced or lost expression of WWOX will lead to development of metabolic disease. In this review, we focus on the roles of WWOX in metabolic disorders and tumors.
    Full-text · Article · Jan 2014 · International journal of biological sciences
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    • "Within this domain, the tyrosine residue 33 of WOX1 has been shown to be critical for binding to partner proteins [7] [8]. The WW domain prefers interaction with a proline-rich motif with the consensus amino acid sequence ''PPXY'', which is present in many WOX1-binding proteins [1]. Latent membrane protein 2A (LMP2A) of Epstein–Barr virus (EBV) is frequently expressed in EBV-associated human malignancies including nasopharyngeal carcinoma (NPC) [9] [10]. "
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    ABSTRACT: WW domain-containing oxidoreductase (WOX1) participates in tumor suppression and many other biologic functions, but its molecular and functional interactions with viral proteins remain largely unknown. This study reveals that WOX1 is physically associated with latent membrane protein 2A (LMP2A), an oncoprotein of Epstein-Barr virus. The molecular interaction involves the tyrosine residue 33 of WOX1 and the proline-rich motifs of LMP2A. Interestingly, endogenous WOX1 is required for some LMP2A-triggered, cancer-promoting effects, including activation of extracellular signal-regulated kinase-1/2, upregulation of matrix metalloproteinase 9 (MMP9), and promotion of cell invasion. Upon knockdown of endogenous WOX1, LMP2A-triggered MMP9 induction is restored by exogenous wild-type WOX1, but not by a WOX1 mutant defective in LMP2A binding. These results indicate that, through interaction with LMP2A, WOX1 is involved in MMP9 induction, suggesting a novel role of WOX1 in Epstein-Barr virus-associated cancer progression.
    Full-text · Article · Jun 2013 · Biochemical and Biophysical Research Communications
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    • "The first WW domain of WWOX may interact with proteins possessing a PPxY motif(s) such as AP-2γ, p73, ErbB4, Ezrin, SIMPLE, c-Jun, RUNX4, and many others (Chang et al., 2007; Salah et al., 2012; Su et al., 2012; Figure 1). Transiently overexpressed WWOX binds transcription factors AP-2, p73, and c-Jun and block their nuclear relocation in vitro, which suppresses cancer cell survival (Salah et al., 2012). "
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    ABSTRACT: Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.
    Full-text · Article · Mar 2013 · Frontiers in Oncology
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