Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species

O’Keefe, Louise V.; Colella, Alexander; Dayan, Sonia; Chen, Qingwen; Choo, Amanda; Jacob, Reuben; Price, Gareth; Venter, Dean; Richards, Robert I.

doi:10.1093/hmg/ddq495

Cited by 54 publications

(86 citation statements)

References 49 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reports of functional interactions of dWWOX in the animal models described earlier in this review have shown that it functionally interacts with mitochondrial proteins including isocitrate dehydrogenase (IDH) and superoxide dismutase (SOD1) (45). These results led to the proposal that WWOX plays a role in regulating reactive oxygen species (ROS) and mitochondrial metabolism.…”

Section: Wwox and Metabolismmentioning

confidence: 84%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

Section: Wwox and Metabolismmentioning

confidence: 84%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In stark contrast, functional deficiency of WWOX in Drosophila does not generate the disease phenotypes in the neural system. 25 …”

Section: Wwox In Neural Diseasesmentioning

confidence: 99%

Introduction to a Thematic Issue for WWOX

Chang

2015

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.

show abstract

“…Although the WW2 domain of WWOX has an atypical structure, due to replacement of tyrosine instead of tryptophan, it was suggested that it belongs to Group I (25). Recently, a proteomic screen of the Drosophila orthologue of WWOX revealed putative interacting partners, although none of the proteins identified had PY motifs (26). Nevertheless, a comprehensive interactive proteome of mammalian WWOX WW domains is lacking.…”

mentioning

confidence: 99%

Characterizing WW Domain Interactions of Tumor Suppressor WWOX Reveals Its Association with Multiprotein Networks

Abu-Odeh

Bar-Mag

Huang

et al. 2014

Journal of Biological Chemistry

121

View full text Add to dashboard Cite

Background: WWOX encodes a 46-kDa tumor suppressor. Results: WW1 domain of WWOX mediates its protein-protein interaction with PY motifs that are involved in molecular processes, including transcription, RNA processing, and metabolism. Conclusion: The WW1 domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks. Significance: This study provides a better understanding of WWOX biology in normal and disease states.

show abstract

Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species

Cited by 54 publications

References 49 publications

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Introduction to a Thematic Issue for WWOX

Characterizing WW Domain Interactions of Tumor Suppressor WWOX Reveals Its Association with Multiprotein Networks

Contact Info

Product

Resources

About