Functional association between Wwox tumor suppressor protein and p73, a p53 homolog

Aqeilan, Rami I.; Pekarsky, Yuri; Herrero, Juan J.; Palamarchuk, Alexey; Letofsky, Jean; Druck, Teresa; Trapasso, Francesco; Han, Shuang; Melino, Gerry; Huebner, Kay; Croce, Carlo M.

doi:10.1073/pnas.0400805101

Cited by 213 publications

(294 citation statements)

References 21 publications

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“…Our observation that the inhibition of endogenous WWOX expression enhances the effect of Wnt-3a on b-catenin stability supports this hypothesis. WWOX has earlier been shown to associate with p73, AP2-g, c-Jun and ErbB-4 in the cytoplasm and prevents their translocation into the nucleus, thereby inhibiting their transcriptional activity (Aqeilan et al, 2004a(Aqeilan et al, , 2004bGaudio et al, 2006). The sequestration of protein in the perinuclear compartment by WWOX seems, therefore, to be an important mechanism antagonizing the function of various proteins involved in the modulation of transcription, including Dvl proteins, in this study.…”

Section: Discussionsupporting

confidence: 51%

“…These results suggest strongly that WWOX does not inhibit the Wnt/ b-catenin pathway by disrupting the interaction of Dvl-2 with the b-catenin-degradation complex. (Aqeilan et al, 2004a(Aqeilan et al, , 2004bGaudio et al, 2006). These results and ours therefore raise the possibility that WWOX would inhibit the transcriptional activity of the Wnt/b-catenin signaling pathway by preventing the entry of Dvl into the nucleus.…”

Section: Binding Domainssupporting

confidence: 60%

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Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/b-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/b-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on b-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/b-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Section: Discussionsupporting

confidence: 51%

Section: Binding Domainssupporting

confidence: 60%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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“…p73 localizes to mitochondria AE Sayan et al through the PPXY motif located at the p73 C terminus (amino acids between 482 and 488; Aqeilan et al, 2004). Although we could not map the internal cleavage sites in p73, all detected p73 fragments (F1, F2 and F3) should contain the PPXY motif as they are detected by p73SAM antibody that is raised against amino-acid residues 487-554 of TAp73a.…”

Section: Discussionmentioning

confidence: 72%

“…Although we could not map the internal cleavage sites in p73, all detected p73 fragments (F1, F2 and F3) should contain the PPXY motif as they are detected by p73SAM antibody that is raised against amino-acid residues 487-554 of TAp73a. This interaction induces the shuttle of p73 from nucleus to cytoplasm in an Srcdependent manner and increases the apoptotic activity of Wwox protein (Aqeilan et al, 2004). Therefore, a further possibility is that p73 or p73 cleavage fragments migrate to the cytoplasm/mitochondria following interaction with WW domain containing proteins.…”

Section: Discussionmentioning

confidence: 99%

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

Sayan

Gogvadze

et al. 2008

Oncogene

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The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcriptionindependent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.

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“…4 WWOX is known to participate in several physiological functions through interaction with several regulators, such as Dvl proteins for the regulation of Wnt-catenin pathway, 5 JNK and c-Jun for JNK signaling, 4,6 RUNX2 for osteoblast differentiation 7 , and p53/p73 for apoptosis. 8,9 Previous report showed that WWOX is a novel regulator in extracellular signal-regulated kinase (ERK) signaling through interaction with MEK2. 10 ERK signaling is important for the control of cell proliferation, migration, cell division, and differentiation.…”

mentioning

confidence: 99%

WWOX Induces MEK2-Mediated Cell Death in a p53 Independent Manner

Cho

2012

Bulletin of the Korean Chemical Society

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WW domain-containing oxidoreductase WWOX that contains two WW domains in the N-terminus, which are involved in protein-protein interactions, and an alcohol dehydrogenase (ADH) domain is a putative tumor suppressor and a proapoptotic protein. It has been reported that WWOX gene is located at the common fragile site FRA16D in chromosome 16q23.3-24.1 and its expression is downregulated in various cancer types. 1,2 Furthermore, aberrantly spliced WWOX mRNA forms that were not detected in normal cells were detected in cancer cell lines and primary breast tumors. 3 In addition, loss of WWOX expression resulted in resistance to apoptosis induced by tumor necrosis factor, staurosporine, UV, and p53 overexpression whereas overexpressed WWOX promoted apoptosis synergistically with p53. 4 WWOX is known to participate in several physiological functions through interaction with several regulators, such as Dvl proteins for the regulation of Wnt-catenin pathway, 5 JNK and c-Jun for JNK signaling, 4,6 RUNX2 for osteoblast differentiation 7 , and p53/p73 for apoptosis. 8,9 Previous report showed that WWOX is a novel regulator in extracellular signal-regulated kinase (ERK) signaling through interaction with MEK2. 10 ERK signaling is important for the control of cell proliferation, migration, cell division, and differentiation. 11 ERK is phosphorylated and activated by MAP kinase kinases (MAP2Ks) such as MEK1/2. However, ERK activated by either MEK1 or MEK2 might have opposite roles in cell survival. MEK1/ERK signal enhances cell proliferation, whereas the MEK2/ERK induces growth arrest at the G 1 /S boundary. 12 Since the previous study showed that WWOX interacts with MEK2 and activates ERK pathway 10 and WWOX is a putative tumor suppressor, it implicates that the association of WWOX with MEK2 may have a negative role in cell growth.In this study, it was investigated whether WWOX regulates MEK2-mediated cell growth. Since ERK activity is increased by WWOX, 10 cell viability assays were carried out to test whether WWOX regulates MEK2-induced proliferation of HEK 293 cells. HEK 293 cells were transiently co-transfected with FLAG-tagged WWOX wild-type (WT) and HAtagged MEK2 expression plasmids. To enhance MEK2 activity and susceptibility to apoptosis, cells were treated with 0.5 mM H 2 O 2 for 16 h prior to assay. WWOX-induced cell death was significantly increased in the presence of MEK2 while MEK2 alone did not induce cell death (Fig. 1), indicating that WWOX enhances MEK2-mediated cell death.H 2 O 2 decreases the cellular threshold for cell death induction by inducing pro-apoptotic events. The threshold concentration of H 2 O 2 which affects WWOX/MEK2-mediated cell viability was investigated. HEK 293 cells co-transfected with FLAG-WWOX WT and HA-MEK2 expression plasmids were treated with various concentrations of H 2 O 2 for 16 h prior to viability assays. Cells transfected with WWOX or MEK2 alone did not show any change of cell viability in the absence of H 2 O 2 and those treated with 1 mM were severely decreased in cell viabil...

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Functional association between Wwox tumor suppressor protein and p73, a p53 homolog

Cited by 213 publications

References 21 publications

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

WWOX Induces MEK2-Mediated Cell Death in a p53 Independent Manner

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