Tumor Suppressor WWOX Contributes to the Elimination of Tumorigenic Cells in Drosophila melanogaster

O’Keefe, Louise V.; Lee, Cheng Shoou; Choo, Amanda; Richards, Robert I.

doi:10.1371/journal.pone.0136356

Cited by 16 publications

(26 citation statements)

References 68 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). In contrast, little is known about neurological related phenotypes in dWWOX loss in D. melanogaster.…”

Section: Drosophila Melanogaster: Connecting Wwox To Metabolismsupporting

confidence: 67%

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: Drosophila Melanogaster: Connecting Wwox To Metabolismsupporting

confidence: 67%

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

“…One of the most striking features of our RNA-Seq data was increased expression of a number of genes associated with the response to oxidative stress (Table 2). These ranged from signaling proteins like TNF-associated Factor 4 (TRAF4), which acts upstream of the JNK pathway to regulate the oxidative stress response (TANG et al 2013), to enzymes like WW domain containing oxidoreductase (WWOX), which regulates ROS and TNF-induced cell death (O'KEEFE et al 2015), or CG3714, a Nicotinate phosphoribosyltransferase family member that is essential for the increase in cellular NAD levels to prevent oxidative stress (HARA et al 2007). Among these, multiple Glutathione S-transferase (GST) genes were upregulated in both sas-4 and asl mutants, and sas-4 loss led to upregulation of three additional GSTD genes ( Figure 4A).…”

Section: Centrosome Loss Leads To Oxidative Stressmentioning

confidence: 99%

“…However, trying to fit all the data into a single, simple linear pathway is difficult. Directly inducing apoptosis or triggering caspase activity without death can lead to ROS elevation(HUU et al 2015;SANTABARBARA-RUIZ et al 2015;FOGARTY et al 2016;KHAN et al 2017;PEREZ et al 2017) but it is also wellestablished that elevating ROS can trigger apoptosis(CAMHI et al 1995; MARTINDALE AND HOLBROOK 2002; REDZA-DUTORDOIR AND AVERILL-BATES 2016), and reducing ROS can limit the apoptotic response(O'KEEFE et al 2015;CLEMENTE-RUIZ et al 2016;FOGARTY et al 2016). There is evidence that ROS production is induced by JNK-signaling(KHAN et al 2017;PEREZ et al 2017), but also evidence that ROS plays a role in activating JNK(WANG et al 2003;OHSAWA et al 2012;SANTABARBARA-RUIZ et al 2015;CLEMENTE- RUIZ et al 2016;FOGARTY et al 2016;KHAN et al 2017;PEREZ et al 2017), and that JNK signaling can induce an antioxidant response(WANG et al 2003).…”

mentioning

confidence: 99%

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

Poulton

McKay

Peifer³

2018

Preprint

View full text Add to dashboard Cite

Centrosomes play a critical role in mitotic spindle assembly through their role in microtubule nucleation and bipolar spindle assembly. Loss of centrosomes can impair the ability of some cells to properly conduct mitotic division, leading to chromosomal instability, cell stress, and aneuploidy. Multiple aspects of the cellular response to mitotic error associated with centrosome loss appears to involve activation of JNK signaling. To further characterize the transcriptional effects of centrosome loss, we compared gene expression profiles of wildtype and acentrosomal cells from Drosophila wing imaginal discs. We found elevation of expression of JNK target genes, which we verified at the protein level. Consistent with this, the upregulated gene set showed significant enrichment for the AP1 consensus DNA binding sequence. We also found significant elevation in expression of genes regulating redox balance. Based on those findings, we examined oxidative stress after centrosome loss, revealing that acentrosomal wing cells have significant increases in reactive oxygen species (ROS). We then performed a candidate genetic screen and found that one of the genes upregulated in acentrosomal cells, G6PD, plays an important role in buffering acentrosomal cells against increased ROS and helps protect those cells from cell death. Our data and other recent studies have revealed a complex network of signaling pathways, transcriptional programs, and cellular processes that epithelial cells use to respond to stressors like mitotic errors to help limit cell damage and maintain normal tissue development.

show abstract

“…When cytosolic WWOX protein relocates to the nucleus under stress conditions, WWOX is able to maintain genomic stability by controlling ATM activation and DNA damage response (Abu-Odeh et al, 2014; Abu-Remaileh et al, 2015). Most recently, WWOX-mediated suppression of cancer cell growth has been established in Drosophila (O'Keefe et al, 2015). Notably, null mutations of WWOX/Wwox gene in humans and animals lead to severe neural diseases (e.g., microcephaly, seizure, ataxia, etc.…”

Section: Tumor Suppressor Wwox Is Anchored On the Cell Membrane By Hymentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

show abstract

Tumor Suppressor WWOX Contributes to the Elimination of Tumorigenic Cells in Drosophila melanogaster

Cited by 16 publications

References 68 publications

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Contact Info

Product

Resources

About