Conditional inactivation of the mouse <i>Wwox</i> tumor suppressor gene recapitulates the null phenotype

Abdeen, Suhaib K.; Mare, Sara Del; Hussain, Sadeeq; Abu-Remaileh, Muhannad; Salah, Zaidoun; Hagan, John P.; Rawahneh, Maysoon; Pu, Xin; Russell, Stacey; Stein, Janet L.; Lian, Jane B.; Aqeilan, Rami I.

doi:10.1002/jcp.24308

Cited by 36 publications

(45 citation statements)

References 23 publications

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“…Furthermore, these same Wwox-null mice exhibited spontaneous and audiogenic seizures (20), 4 which, in retrospect, is a finding remarkably consistent with recent studies linking WWOX and neurodegenerative diseases described later in this review. These phenotypes were recapitulated in other mouse models carrying a conditional loxp site when bred with a general delete EllA-Cre (21,22), confirming WWOX in vivo requirement for these phenotypes.…”

Section: Rodent Models: Initial Studies On Wwox and Cancer And Beyondsupporting

confidence: 58%

“…Drosophila models have in particular contributed to the further appreciation of WWOX's role in regulating mitochondrial metabolism (discussed in detail later in this review). By demonstrating the association of WWOX loss or its reduced expression (using siRNA) with enhanced aerobic glycolysis and reduced mitochondrial function (11), the D. melanogaster model supports the association between WWOX and metabolic function that was noted earlier on in the rodent models described above (15,17,22). Furthermore, altered levels of WWOX in D. melanogaster were recently shown to eliminate tumorigenic cells in the fly through TNF␣/Egr modulation leading to caspase-3 activity alteration and cell death promotion (25).…”

Section: Drosophila Melanogaster: Connecting Wwox To Metabolismmentioning

confidence: 58%

“…These knockdown fish displayed additional changes associated with growth retardation, postnatal lethality, altered calcium dynamics, and bone defects: phenotypes that very much resemble the Wwox-null mice (15,17,22). Thus, the zebrafish could serve as an additional vertebrate model for understanding molecular mechanisms of WWOX loss in human diseases (27).…”

Section: Zebrafish: Another Potential Model Organism For the Study Ofmentioning

confidence: 96%

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Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

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WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic-and CNS-associated functions and their underlying molecular basis.The WWOX gene initially became a research target due to its localization in a region of considerable chromosomal instability (16q23.2), at common fragile site (CFS) 3 FRA16D, which immediately marked it as a possible tumor suppressor gene (TSG) (1, 2). Inactivation of TSGs at CFSs has long been known as a hallmark of cancer (3). CFSs are evolutionarily conserved genomic regions that are sensitive to replicative stress (4). In 2010, Beroukhim et al. (5) demonstrated that deletion of TSGs spanning CFSs is among the most significant driver events in cancer. Although highly recombinogenic, CFSs are rarely involved in oncogenic activation, suggesting that CFSs are mainly hot spots for inactivation of tumor suppressors (3). A number of animal studies were conducted on WWOX, and in keeping with the above paradigm, many insights were gained into WWOX's association with cancer development (reviewed elsewhere (6 -10)). However, a few surprising results led the research in other unanticipated directions, linking WWOX to regulation of metabolic function, as well as neuronal development (Fig. 1). These animal model studies were complemented by studies on the cellular and molecular levels, modeling WWOX structure and identifying its potential binding partners, thus generating a comprehensive functional model of WWOX activity.This review sketches out how our view of WWOX has evolved over the years, with emphasis on the recent findings that link WWOX to metabolic regulation and CNS homeostasis. We begin with an overview of the original WWOX animal model studies, followed by an outline of subsequent WWOX research performed at the cellular and molecular levels. We review potential WWOX binding partners and their associated cellular pathways. We further define WWOX structure and architecture, expounding its behavior in the context of its two tandem WW domains and expansive short-chain dehydrogenase/reductase (SDR) region. Taken together, we generate a functional model of WWOX that highlights the versatility of this protein and suggests possible new directions for further study of WWOX's complex nature. Animal Model...

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Section: Rodent Models: Initial Studies On Wwox and Cancer And Beyondsupporting

confidence: 58%

Section: Drosophila Melanogaster: Connecting Wwox To Metabolismmentioning

confidence: 58%

Section: Zebrafish: Another Potential Model Organism For the Study Ofmentioning

confidence: 96%

See 1 more Smart Citation

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

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“…6,7 At this point, however, it remains unclear what are the basis for the molecular defects underlying this lethal hypoglycemia. Notably, juvenile Wwox KO mice and haploinsufficient heterozygous mice display higher incidence of tumor formation.…”

mentioning

confidence: 99%

Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

2014

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The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1a (HIF1a) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1a and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1a levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwoxdeficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism. Cell Death and Differentiation (2014) 21, 1805-1814; doi:10.1038/cdd.2014.95; published online 11 July 2014The WW domain-containing oxidoreductase (WWOX) spans one of the most active common fragile sites involved in cancer, FRA16D. WWOX encodes a 46-kDa protein that contains two N-terminal WW domains and a central shortchain dehydrogenase/reductase domain.1,2 Loss of WWOX expression has been identified in a variety of tumors (reviewed in Gardenswartz and Aqeilan 3 ). In order to understand the role of WWOX as tumor suppressor, Wwox knockout (KO) mice were generated. 4 At birth, homozygous Wwox-deficient pups were indistinguishable from wild-type (WT) or heterozygous littermates; at 3 days, homozygous pups were smaller than littermates 4 and all Wwox KO mice died by 4 weeks after birth because of severe metabolic defects, mainly hypoglycemia.5 Similar results were obtained in Wwox-conditional mouse models. 6,7 At this point, however, it remains unclear what are the basis for the molecular defects underlying this lethal hypoglycemia. Notably, juvenile Wwox KO mice and haploinsufficient heterozygous mice display higher incidence of tumor formation. 4,8,9 At the molecular level, it has been shown that WWOX, via its WW1 domain, interacts with proline-tyrosin motif-containing proteins including AP-2g, 10 ErbB4, 11 c-Jun 12 and others 13 and inhibits their transcriptional function. In a recent mass spectrometry analysis, we demonstrated that indeed the WW1 domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks, including metabolism.14 Recently, it has been also shown that WWOX may interact with isocitrate dehydrogenase and malate dehydrogenase in Drosophila. 15Furthermore, it has been reported that alteration in metabolism affects WWOX transcripts. 16 Critically, however, it is ...

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“…43 Other reports also support the findings that homozygous WWOX gene-trap mice have shorter lifespan, reduced fertility, and lymphoma formation. 44 The conditional inactivation of WWOX in the germline has shown postnatal lethality and decreased bone formation, 45 while defects have appeared with the conditional deletion of WWOX in mammary glands during mammary branching morphogenesis, but no increased premalignant lesions have been found. 46 Another conditional knockout mouse with the C3H mouse mammary tumor has found mammary carcinoma formation, suggesting the haploinsufficiency of WWOX is cancer predisposing.…”

Section: Wwox In Development and Neoplasmmentioning

confidence: 99%

Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma

Liu

Chiang

Chen

2014

Exp Biol Med (Maywood)

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Glioblastoma multiforme (GBM) is the most aggressive and malignant brain tumor. Delicate microenvironment and lineage heterogeneity of GBM cells including infiltration, hypoxia, angiogenesis, and stemness make them highly resistant to current conventional therapies, with an average life expectancy for GBM patients of less than 15 months. Poor response to cytotoxic agents of GBM cells remains the major challenge of GBM treatment. Resistance of GBM to clinical treatment is a result of genomic alternation and deregulated signaling pathways, such as p53 mutation and apoptosis signaling blockage, providing cancer cells more opportunities for survival rather than cell death. WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene, commonly downregulated in various types of tumors, including GBM. It has been found that the reintroduction of WWOX induced p53-mutant GBM cells to undergo apoptosis, but not in p53 wild-type GBM cells, indicating WWOX is likely to reopen apoptosis pathways in a p53-independent manner in GBM. Identifying the crucial target modulated by WWOX deficiency provides a potential therapeutic target for GBM treatment. Here, we have reviewed the literatures about the role of WWOX in development, signaling pathway, prognosis, and treatment response in malignant glioma.

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Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype

Cited by 36 publications

References 23 publications

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma

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