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Id Subject Object Predicate Lexical cue
T79 0-78 Sentence denotes Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas
T1 0-78 Sentence denotes Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas
T2 80-88 Sentence denotes Abstract
T80 89-251 Sentence denotes Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs.
T3 89-251 Sentence denotes Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs.
T81 252-373 Sentence denotes WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor.
T4 252-373 Sentence denotes WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor.
T82 374-530 Sentence denotes Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade.
T5 374-530 Sentence denotes Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade.
T83 531-664 Sentence denotes Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53.
T6 531-664 Sentence denotes Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53.
T84 665-726 Sentence denotes WWOX is known to physically bind and stabilize wild type p53.
T7 665-726 Sentence denotes WWOX is known to physically bind and stabilize wild type p53.
T85 727-917 Sentence denotes 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.
T8 727-917 Sentence denotes 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.
T86 918-1077 Sentence denotes We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.
T9 918-1077 Sentence denotes We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.
T10 1079-1136 Sentence denotes Mechanisms of Resistance to Temozolomide in Glioblastomas
T875 1137-1276 Sentence denotes Glioblastoma multiforme afflicts 12,500 new patients in the U.S. annually (Friedman et al., 2000; Stupp et al., 2009; Silber et al., 2012).
T11 1137-1276 Sentence denotes Glioblastoma multiforme afflicts 12,500 new patients in the U.S. annually (Friedman et al., 2000; Stupp et al., 2009; Silber et al., 2012).
T876 1277-1468 Sentence denotes Glioblastoma (GBM) is highly lethal, and the average survival expectancy is 14.6 months, and the overall 5-year survival rate for GBM is only 9.8% (Friedman et al., 2000; Stupp et al., 2009).
T12 1277-1468 Sentence denotes Glioblastoma (GBM) is highly lethal, and the average survival expectancy is 14.6 months, and the overall 5-year survival rate for GBM is only 9.8% (Friedman et al., 2000; Stupp et al., 2009).
T877 1469-1622 Sentence denotes High levels of resistance to current therapeutic modalities and cancer relapse are frequently seen in patients (Haar et al., 2012; Happold et al., 2012).
T13 1469-1622 Sentence denotes High levels of resistance to current therapeutic modalities and cancer relapse are frequently seen in patients (Haar et al., 2012; Happold et al., 2012).
T878 1623-1829 Sentence denotes The current standard therapy for GBM mainly includes maximum debulking surgery, radiation, and treatment with the monofunctional alkylating agent temozolomide (TMZ) (Friedman et al., 2000; Nishikawa, 2010).
T14 1623-1829 Sentence denotes The current standard therapy for GBM mainly includes maximum debulking surgery, radiation, and treatment with the monofunctional alkylating agent temozolomide (TMZ) (Friedman et al., 2000; Nishikawa, 2010).
T879 1830-2220 Sentence denotes Multiple mechanisms are involved in the TMZ resistance, which may include cancer stem cells, microRNAs, drug efflux, DNA damage repair, tumor cells under hypoxia, histone deacetylation, epithelial-mesenchymal transition, STAT3 kinase, and many others (Haar et al., 2012; Happold et al., 2012; Johannessen and Bjerkvig, 2012; Kitange et al., 2012; Kohsaka et al., 2012; Zhang et al., 2012b).
T15 1830-2220 Sentence denotes Multiple mechanisms are involved in the TMZ resistance, which may include cancer stem cells, microRNAs, drug efflux, DNA damage repair, tumor cells under hypoxia, histone deacetylation, epithelial-mesenchymal transition, STAT3 kinase, and many others (Haar et al., 2012; Happold et al., 2012; Johannessen and Bjerkvig, 2012; Kitange et al., 2012; Kohsaka et al., 2012; Zhang et al., 2012b).
T880 2221-2381 Sentence denotes Temozolomide induces generation of DNA lesions, including O6-methylguanine, N3-methyladenine, and N7-methylguanine (Goellner et al., 2011; Zhang et al., 2012b).
T16 2221-2381 Sentence denotes Temozolomide induces generation of DNA lesions, including O6-methylguanine, N3-methyladenine, and N7-methylguanine (Goellner et al., 2011; Zhang et al., 2012b).
T881 2382-2507 Sentence denotes The O6-methylguanine lesion is known to trigger autophagy, rather than apoptosis, to cause cell death (Kanzawa et al., 2003).
T17 2382-2507 Sentence denotes The O6-methylguanine lesion is known to trigger autophagy, rather than apoptosis, to cause cell death (Kanzawa et al., 2003).
T882 2508-2674 Sentence denotes Also, inhibition of antiapoptotic Bcl-2 by a pan-Bcl-2 inhibitor (−)-gossypol leads to autophagic death in gliomas and enhances the action of TMZ (Voss et al., 2010).
T18 2508-2674 Sentence denotes Also, inhibition of antiapoptotic Bcl-2 by a pan-Bcl-2 inhibitor (−)-gossypol leads to autophagic death in gliomas and enhances the action of TMZ (Voss et al., 2010).
T883 2675-2830 Sentence denotes However, a recent study demonstrated that TMZ-induced autophagy is pro-survival, and may block the eventual apoptosis in GBM cells (Knizhnik et al., 2013).
T19 2675-2830 Sentence denotes However, a recent study demonstrated that TMZ-induced autophagy is pro-survival, and may block the eventual apoptosis in GBM cells (Knizhnik et al., 2013).
T884 2831-2945 Sentence denotes Also, MAPO2 (C1orf201) gene participates in the O6-methylguanine lesion-induced apoptosis (Fujikane et al., 2012).
T20 2831-2945 Sentence denotes Also, MAPO2 (C1orf201) gene participates in the O6-methylguanine lesion-induced apoptosis (Fujikane et al., 2012).
T885 2946-2988 Sentence denotes MAPO2 gene encodes a novel 37-kDa protein.
T21 2946-2988 Sentence denotes MAPO2 gene encodes a novel 37-kDa protein.
T886 2989-3053 Sentence denotes It is not determined whether this gene is involved in autophagy.
T22 2989-3053 Sentence denotes It is not determined whether this gene is involved in autophagy.
T887 3054-3251 Sentence denotes The O6-methylguanine lesion is a substrate for direct repair by O6-methylguanine-DNA methyltransferase (MGMT) (Pollack et al., 2006; Hegi et al., 2008; Fukushima et al., 2009; Zhang et al., 2012b).
T23 3054-3251 Sentence denotes The O6-methylguanine lesion is a substrate for direct repair by O6-methylguanine-DNA methyltransferase (MGMT) (Pollack et al., 2006; Hegi et al., 2008; Fukushima et al., 2009; Zhang et al., 2012b).
T888 3252-3500 Sentence denotes Without MGMT repair, O6-methylguanine initiates activation of mismatch repair-deficient (MMR) proteins or Rad3-related protein kinase that ultimately leads to apoptotic cell death (Caporali et al., 2004; Wang and Edelmann, 2006; Roos et al., 2007).
T24 3252-3500 Sentence denotes Without MGMT repair, O6-methylguanine initiates activation of mismatch repair-deficient (MMR) proteins or Rad3-related protein kinase that ultimately leads to apoptotic cell death (Caporali et al., 2004; Wang and Edelmann, 2006; Roos et al., 2007).
T889 3501-3672 Sentence denotes High expression of MGMT or loss of MMR contributes significantly to TMZ resistance in many clinical cases (Pollack et al., 2006; Hegi et al., 2008; Sarkaria et al., 2008).
T25 3501-3672 Sentence denotes High expression of MGMT or loss of MMR contributes significantly to TMZ resistance in many clinical cases (Pollack et al., 2006; Hegi et al., 2008; Sarkaria et al., 2008).
T890 3673-3750 Sentence denotes The initiation of apoptotic signaling fails in the absence of the MMR system.
T26 3673-3750 Sentence denotes The initiation of apoptotic signaling fails in the absence of the MMR system.
T891 3751-3910 Sentence denotes Sensitivity to TMZ is significantly associated with the methylation status of MGMT gene promoter in cells committed to differentiation (Villalva et al., 2012).
T27 3751-3910 Sentence denotes Sensitivity to TMZ is significantly associated with the methylation status of MGMT gene promoter in cells committed to differentiation (Villalva et al., 2012).
T892 3911-4029 Sentence denotes An increase in MGMT gene promoter methylation, which blocks MGMT protein expression, prolongs cancer patient survival.
T28 3911-4029 Sentence denotes An increase in MGMT gene promoter methylation, which blocks MGMT protein expression, prolongs cancer patient survival.
T893 4030-4176 Sentence denotes Intriguingly, overexpressed microRNA-21 reduces Bax/Bcl-2 ratio and caspase-3 activity, thereby blocking TMZ-induced apoptosis (Shi et al., 2010).
T29 4030-4176 Sentence denotes Intriguingly, overexpressed microRNA-21 reduces Bax/Bcl-2 ratio and caspase-3 activity, thereby blocking TMZ-induced apoptosis (Shi et al., 2010).
T894 4177-4263 Sentence denotes MicroRNA-21 is considered as a pro-survival factor for cancer cells (Li et al., 2012).
T30 4177-4263 Sentence denotes MicroRNA-21 is considered as a pro-survival factor for cancer cells (Li et al., 2012).
T895 4264-4567 Sentence denotes Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. α5β1 integrin negatively regulates p53 signaling, and the event induces glioma cell resistance to TMZ (Janouskova et al., 2012). α5β1 integrin is considered as a therapeutic target for high-grade brain tumors.
T31 4264-4567 Sentence denotes Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. α5β1 integrin negatively regulates p53 signaling, and the event induces glioma cell resistance to TMZ (Janouskova et al., 2012). α5β1 integrin is considered as a therapeutic target for high-grade brain tumors.
T896 4568-4778 Sentence denotes The base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG), which repairs the cytotoxic lesions N3-methyladenine and N7-methylguanine, also participates in the TMZ resistance (Agnihotri et al., 2012).
T32 4568-4778 Sentence denotes The base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG), which repairs the cytotoxic lesions N3-methyladenine and N7-methylguanine, also participates in the TMZ resistance (Agnihotri et al., 2012).
T897 4779-5000 Sentence denotes Upregulation of mitochondrial respiratory chain coupling to suppress the production of reactive oxygen species (ROS) regulated by cytochrome c oxidase contributes in part to TMZ resistance in gliomas (Oliva et al., 2011).
T33 4779-5000 Sentence denotes Upregulation of mitochondrial respiratory chain coupling to suppress the production of reactive oxygen species (ROS) regulated by cytochrome c oxidase contributes in part to TMZ resistance in gliomas (Oliva et al., 2011).
T898 5001-5152 Sentence denotes Reversal of TMZ resistance may be achieved by MGMT pseudosubstrates, O6-benzylguanine and lomeguatrib to sensitize tumors to TMZ (Zhang et al., 2012b).
T34 5001-5152 Sentence denotes Reversal of TMZ resistance may be achieved by MGMT pseudosubstrates, O6-benzylguanine and lomeguatrib to sensitize tumors to TMZ (Zhang et al., 2012b).
T899 5153-5358 Sentence denotes Methoxyamine-blocker of base excision repair contributes significantly to TMZ cytotoxicity particularly when O6-methylguanine adducts are repaired or tolerated (Goellner et al., 2011; Zhang et al., 2012b).
T35 5153-5358 Sentence denotes Methoxyamine-blocker of base excision repair contributes significantly to TMZ cytotoxicity particularly when O6-methylguanine adducts are repaired or tolerated (Goellner et al., 2011; Zhang et al., 2012b).
T900 5359-5518 Sentence denotes Dual targeting of base excision repair and NAD(+) biosynthesis may reverse TMZ resistance in patients with resistant and recurrent GBM (Goellner et al., 2011).
T36 5359-5518 Sentence denotes Dual targeting of base excision repair and NAD(+) biosynthesis may reverse TMZ resistance in patients with resistant and recurrent GBM (Goellner et al., 2011).
T901 5519-5703 Sentence denotes Interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increase the sensitivity of TMZ through MGMT-dependent or -independent mechanisms (Nakada et al., 2012).
T37 5519-5703 Sentence denotes Interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increase the sensitivity of TMZ through MGMT-dependent or -independent mechanisms (Nakada et al., 2012).
T902 5704-5817 Sentence denotes Resveratrol, a natural polyphenol, reverses TMZ resistance via an NF-κB-dependent mechanism (Huang et al., 2012).
T38 5704-5817 Sentence denotes Resveratrol, a natural polyphenol, reverses TMZ resistance via an NF-κB-dependent mechanism (Huang et al., 2012).
T903 5818-5929 Sentence denotes STAT3 inhibitor or STAT3 knockdown potentiates TMZ efficacy in resistant GBM cell lines (Kohsaka et al., 2012).
T39 5818-5929 Sentence denotes STAT3 inhibitor or STAT3 knockdown potentiates TMZ efficacy in resistant GBM cell lines (Kohsaka et al., 2012).
T904 5930-6030 Sentence denotes Intratumoral hypoxia is common in GBMs and may be associated with the development of TMZ resistance.
T40 5930-6030 Sentence denotes Intratumoral hypoxia is common in GBMs and may be associated with the development of TMZ resistance.
T905 6031-6118 Sentence denotes Induced hyperoxia can be utilized to reverse TMZ resistance in GBMs (Sun et al., 2012).
T41 6031-6118 Sentence denotes Induced hyperoxia can be utilized to reverse TMZ resistance in GBMs (Sun et al., 2012).
T906 6119-6186 Sentence denotes Cancer stem cells are probably the key to failure in TMZ treatment.
T42 6119-6186 Sentence denotes Cancer stem cells are probably the key to failure in TMZ treatment.
T907 6187-6375 Sentence denotes The concept of cancer stem cell survival from treatment with TMZ and other chemotherapeutic drugs has been more complicated than previously thought (Beier et al., 2011; Chen et al., 2012).
T43 6187-6375 Sentence denotes The concept of cancer stem cell survival from treatment with TMZ and other chemotherapeutic drugs has been more complicated than previously thought (Beier et al., 2011; Chen et al., 2012).
T908 6376-6502 Sentence denotes CD133-positive cancer stem cells are expressed in both normal stem cells and cancer stem cells (Donovan and Pilkington, 2012).
T44 6376-6502 Sentence denotes CD133-positive cancer stem cells are expressed in both normal stem cells and cancer stem cells (Donovan and Pilkington, 2012).
T909 6503-6633 Sentence denotes However, the role of CD133 as a marker for glioma cancer stem cells relative to its biological function has yet to be established.
T45 6503-6633 Sentence denotes However, the role of CD133 as a marker for glioma cancer stem cells relative to its biological function has yet to be established.
T46 6635-6675 Sentence denotes WW Domain-Containing Oxidoreductase WWOX
T3823 6676-6798 Sentence denotes Recently, tumor suppressors p53 and WWOX were shown to regulate the apoptosis of glioblastoma cells (Chiang et al., 2012).
T47 6676-6798 Sentence denotes Recently, tumor suppressors p53 and WWOX were shown to regulate the apoptosis of glioblastoma cells (Chiang et al., 2012).
T3824 6799-6909 Sentence denotes WW domain-containing oxidoreductase, known as WWOX, FOR, or WOX1, is encoded by human or mouse WWOX/Wwox gene.
T48 6799-6909 Sentence denotes WW domain-containing oxidoreductase, known as WWOX, FOR, or WOX1, is encoded by human or mouse WWOX/Wwox gene.
T3825 6910-7007 Sentence denotes This gene is located in chromosome 16q23.3–24.1, an area known as the common fragile site FRA16D.
T49 6910-7007 Sentence denotes This gene is located in chromosome 16q23.3–24.1, an area known as the common fragile site FRA16D.
T3826 7008-7299 Sentence denotes The full-length WWOX protein is composed of two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a proapoptotic C-terminal tail D3 (Chang et al., 2001, 2007, 2010; Aqeilan et al., 2004, 2007; Hong et al., 2007; Salah et al., 2012) (Figure 1).
T50 7008-7299 Sentence denotes The full-length WWOX protein is composed of two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a proapoptotic C-terminal tail D3 (Chang et al., 2001, 2007, 2010; Aqeilan et al., 2004, 2007; Hong et al., 2007; Salah et al., 2012) (Figure 1).
T3827 7300-7500 Sentence denotes WWOX may act as an alternative receptor for sex steroid hormones, since its SDR domain possesses an NSYK motif capable of interacting with androgen and estrogen (Chang et al., 2005a; Su et al., 2012).
T51 7300-7500 Sentence denotes WWOX may act as an alternative receptor for sex steroid hormones, since its SDR domain possesses an NSYK motif capable of interacting with androgen and estrogen (Chang et al., 2005a; Su et al., 2012).
T52 7501-7574 Sentence denotes Figure 1 Schematic diagrams of WWOX structure and its role in signaling.
T12775 7511-7574 Sentence denotes Schematic diagrams of WWOX structure and its role in signaling.
T12776 7575-7703 Sentence denotes WWOX contains two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region.
T53 7575-7703 Sentence denotes WWOX contains two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region.
T12777 7704-7865 Sentence denotes A nuclear localization signal (NLS) is in between the WW domains (Chang et al., 2003, 2007; Del Mare et al., 2011; Salah et al., 2012; Su et al., 2012; reviews).
T54 7704-7865 Sentence denotes A nuclear localization signal (NLS) is in between the WW domains (Chang et al., 2003, 2007; Del Mare et al., 2011; Salah et al., 2012; Su et al., 2012; reviews).
T12778 7866-7921 Sentence denotes The SDR domain possesses a mitochondria-binding region.
T55 7866-7921 Sentence denotes The SDR domain possesses a mitochondria-binding region.
T12779 7922-7995 Sentence denotes There are two conserved tyrosine phosphorylation sites, Tyr33 and Tyr287.
T56 7922-7995 Sentence denotes There are two conserved tyrosine phosphorylation sites, Tyr33 and Tyr287.
T12780 7996-8120 Sentence denotes Other phosphorylation sites predicted by NetPhos 2.0 Server are Tyr6, Thr12, Ser14, Tyr61, Tyr293, and Thr3B3, respectively.
T57 7996-8120 Sentence denotes Other phosphorylation sites predicted by NetPhos 2.0 Server are Tyr6, Thr12, Ser14, Tyr61, Tyr293, and Thr3B3, respectively.
T12781 8121-8192 Sentence denotes Upon stress stimulation, WWOX is phosphorylated in Tyr33 and binds p53.
T58 8121-8192 Sentence denotes Upon stress stimulation, WWOX is phosphorylated in Tyr33 and binds p53.
T12782 8193-8279 Sentence denotes The WWOX/p53 complex then translocates to mitochondria or nucleus to induce apoptosis.
T59 8193-8279 Sentence denotes The WWOX/p53 complex then translocates to mitochondria or nucleus to induce apoptosis.
T12783 8280-8488 Sentence denotes WWOX also binds PPxY motif-containing transcription factors, such as RUNX2, c-Jun, and ERBB4, via its first WW domain, and the binding blocks the activity of these proteins by retaining them in the cytoplasm.
T60 8280-8488 Sentence denotes WWOX also binds PPxY motif-containing transcription factors, such as RUNX2, c-Jun, and ERBB4, via its first WW domain, and the binding blocks the activity of these proteins by retaining them in the cytoplasm.
T12784 8489-8523 Sentence denotes WWOX binds Tau via its SDR domain.
T61 8489-8523 Sentence denotes WWOX binds Tau via its SDR domain.
T12785 8524-8627 Sentence denotes WWOX participates in the Wnt/β-catenin signal pathway by binding Dvl and inhibiting its nuclear import.
T62 8524-8627 Sentence denotes WWOX participates in the Wnt/β-catenin signal pathway by binding Dvl and inhibiting its nuclear import.
T12786 8628-8786 Sentence denotes Phorbol ester stimulates the dissociation of MEK/WWOX complex in Jurkat T cell, and the released WWOX translocates to the mitochondria for causing cell death.
T63 8628-8786 Sentence denotes Phorbol ester stimulates the dissociation of MEK/WWOX complex in Jurkat T cell, and the released WWOX translocates to the mitochondria for causing cell death.
T64 8787-8871 Sentence denotes WWOX is recruited to the membrane area by association with Hyal-2 and phospho-Ezrin.
T12787 8787-8917 Sentence denotes WWOX is recruited to the membrane area by association with Hyal-2 and phospho-Ezrin. Hyal-2 is an alternative receptor for TGF-β1.
T65 8872-8917 Sentence denotes Hyal-2 is an alternative receptor for TGF-β1.
T12788 8918-9066 Sentence denotes In response to TGF-β1, WWOX binds Hyal-2 and forms a complex, followed by relocating to the nucleus and enhancing the SMAD-driven promoter activity.
T66 8918-9066 Sentence denotes In response to TGF-β1, WWOX binds Hyal-2 and forms a complex, followed by relocating to the nucleus and enhancing the SMAD-driven promoter activity.
T12789 9067-9219 Sentence denotes Ack1, activated Cdc42-associated kinase 1; Hyal-2, hyaluronoglucosaminidase 2; CKI, casein kinase; GSK, glycogen synthase kinase; PKA, protein kinase A.
T67 9067-9219 Sentence denotes Ack1, activated Cdc42-associated kinase 1; Hyal-2, hyaluronoglucosaminidase 2; CKI, casein kinase; GSK, glycogen synthase kinase; PKA, protein kinase A.
T3828 9220-9637 Sentence denotes Expression of WWOX is either altered or lost from epigenetic modification in multiple malignant cancers, such as non-small cell lung carcinoma (Donati et al., 2007), hematopoietic malignancies (Ishii and Furukawa, 2004), gastric carcinoma (Aqeilan et al., 2004), pancreatic carcinoma (Kuroki et al., 2004), breast carcinoma (Guler et al., 2004; Aqeilan et al., 2007), and glioblastoma multiforme (Kosla et al., 2011).
T68 9220-9637 Sentence denotes Expression of WWOX is either altered or lost from epigenetic modification in multiple malignant cancers, such as non-small cell lung carcinoma (Donati et al., 2007), hematopoietic malignancies (Ishii and Furukawa, 2004), gastric carcinoma (Aqeilan et al., 2004), pancreatic carcinoma (Kuroki et al., 2004), breast carcinoma (Guler et al., 2004; Aqeilan et al., 2007), and glioblastoma multiforme (Kosla et al., 2011).
T3829 9638-9804 Sentence denotes Restoration of WWOX gene prevents the growth of lung cancer (Fabbri et al., 2005), pancreatic cancer (Nakayama et al., 2008), and prostate cancer (Hong et al., 2009).
T69 9638-9804 Sentence denotes Restoration of WWOX gene prevents the growth of lung cancer (Fabbri et al., 2005), pancreatic cancer (Nakayama et al., 2008), and prostate cancer (Hong et al., 2009).
T3830 9805-10027 Sentence denotes 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).
T70 9805-10027 Sentence denotes 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).
T3831 10028-10212 Sentence denotes 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).
T71 10028-10212 Sentence denotes 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).
T3832 10213-10384 Sentence denotes In stark contrast, Wwox co-migrates with proapoptotic and pro-survival transcription factors to the nuclei of neurons upon sciatic nerve axotomy in rats (Li et al., 2009).
T72 10213-10384 Sentence denotes In stark contrast, Wwox co-migrates with proapoptotic and pro-survival transcription factors to the nuclei of neurons upon sciatic nerve axotomy in rats (Li et al., 2009).
T3833 10385-10474 Sentence denotes No blocking of translocation of transcription factors to the nuclei by Wwox was observed.
T73 10385-10474 Sentence denotes No blocking of translocation of transcription factors to the nuclei by Wwox was observed.
T3834 10475-10647 Sentence denotes Under stress conditions, WWOX is activated via phosphorylation at Tyr33, and binds proteins independently of the PPxY motif (Chang et al., 2001, 2003, 2005a,b, 2007, 2010).
T74 10475-10647 Sentence denotes Under stress conditions, WWOX is activated via phosphorylation at Tyr33, and binds proteins independently of the PPxY motif (Chang et al., 2001, 2003, 2005a,b, 2007, 2010).
T3835 10648-10800 Sentence denotes Activated WWOX physically interacts with serine 46-phosphorylated p53 (Figure 1), which stabilizes p53 and its apoptotic function (Chang et al., 2005b).
T75 10648-10800 Sentence denotes Activated WWOX physically interacts with serine 46-phosphorylated p53 (Figure 1), which stabilizes p53 and its apoptotic function (Chang et al., 2005b).
T3836 10801-10916 Sentence denotes Also, WWOX binds Disheveled proteins (Dvl), which are key components in Wnt/β-catenin signaling pathway (Figure 1).
T76 10801-10916 Sentence denotes Also, WWOX binds Disheveled proteins (Dvl), which are key components in Wnt/β-catenin signaling pathway (Figure 1).
T77 10917-10941 Sentence denotes No PPxY motif is in Dvl.
T3837 10917-11095 Sentence denotes No PPxY motif is in Dvl. Transiently overexpressed WWOX sequesters Dvl-2 in the cytoplasm and thereby blocks Dvl-2-mediated TCF transcriptional activity (Bouteille et al., 2009).
T78 10942-11095 Sentence denotes Transiently overexpressed WWOX sequesters Dvl-2 in the cytoplasm and thereby blocks Dvl-2-mediated TCF transcriptional activity (Bouteille et al., 2009).
T3838 11096-11302 Sentence denotes Overexpressed WWOX induces apoptosis and inhibits proliferation of human hepatic carcinoma cells (Hu et al., 2012) and many cancer cell types (Chang et al., 2007, 2010; Salah et al., 2012; Su et al., 2012).
T79 11096-11302 Sentence denotes Overexpressed WWOX induces apoptosis and inhibits proliferation of human hepatic carcinoma cells (Hu et al., 2012) and many cancer cell types (Chang et al., 2007, 2010; Salah et al., 2012; Su et al., 2012).
T3839 11303-11474 Sentence denotes WWOX enhances the cytotoxic function of tumor necrosis factor by down-regulating apoptosis inhibitor Bcl-2 and Bcl-xL and up-regulating apoptotic p53 (Chang et al., 2001).
T80 11303-11474 Sentence denotes WWOX enhances the cytotoxic function of tumor necrosis factor by down-regulating apoptosis inhibitor Bcl-2 and Bcl-xL and up-regulating apoptotic p53 (Chang et al., 2001).
T3840 11475-11531 Sentence denotes Also, WWOX mediates cell death synergistically with p53.
T81 11475-11531 Sentence denotes Also, WWOX mediates cell death synergistically with p53.
T3841 11532-11801 Sentence denotes Upon exposure to chemicals or environmental stress, such as UV irradiation and chemotherapeutic drugs, WWOX undergoes phosphorylation in Tyr33 and probably others sites, followed by relocating to mitochondria or nuclei for inducing apoptosis (Chang et al., 2007, 2010).
T82 11532-11801 Sentence denotes Upon exposure to chemicals or environmental stress, such as UV irradiation and chemotherapeutic drugs, WWOX undergoes phosphorylation in Tyr33 and probably others sites, followed by relocating to mitochondria or nuclei for inducing apoptosis (Chang et al., 2007, 2010).
T3842 11802-11854 Sentence denotes WWOX binds MEK in Jurkat T cells (Lin et al., 2011).
T83 11802-11854 Sentence denotes WWOX binds MEK in Jurkat T cells (Lin et al., 2011).
T3843 11855-12033 Sentence denotes Phorbol myristate acetate (PMA) dissociates the MEK/WWOX complex and induces WWOX to translocate to the mitochondria to induce apoptosis, whereas MEK relocates to the lipid raft.
T84 11855-12033 Sentence denotes Phorbol myristate acetate (PMA) dissociates the MEK/WWOX complex and induces WWOX to translocate to the mitochondria to induce apoptosis, whereas MEK relocates to the lipid raft.
T3844 12034-12137 Sentence denotes Inhibition of MEK activity increases TMZ-induced suppression of cancer cell growth (Holt et al., 2012).
T85 12034-12137 Sentence denotes Inhibition of MEK activity increases TMZ-induced suppression of cancer cell growth (Holt et al., 2012).
T3845 12138-12307 Sentence denotes Ectopic expression of WWOX in A549 cells induces procaspase-3 and procaspase-9 activation and induces cytochrome C releasing from the mitochondria (Zhang et al., 2012a).
T86 12138-12307 Sentence denotes Ectopic expression of WWOX in A549 cells induces procaspase-3 and procaspase-9 activation and induces cytochrome C releasing from the mitochondria (Zhang et al., 2012a).
T3846 12308-12478 Sentence denotes Complement C1q induces ectopic WWOX phosphorylation in Try33 and leads to cell apoptosis independently of the classical complement activation pathway (Hong et al., 2009).
T87 12308-12478 Sentence denotes Complement C1q induces ectopic WWOX phosphorylation in Try33 and leads to cell apoptosis independently of the classical complement activation pathway (Hong et al., 2009).
T3847 12479-12637 Sentence denotes A portion of WWOX is anchored in the membrane/cytoskeleton area via binding with hyaluronidase Hyal-2 (Hsu et al., 2009) and Phospho-Ezrin (Jin et al., 2006).
T88 12479-12637 Sentence denotes A portion of WWOX is anchored in the membrane/cytoskeleton area via binding with hyaluronidase Hyal-2 (Hsu et al., 2009) and Phospho-Ezrin (Jin et al., 2006).
T3848 12638-12854 Sentence denotes Transforming growth factor β1 binds Hyal-2 as a cognate receptor to signal the formation of the WWOX/Hyal-2/Smad4 complex to relocate to the nucleus for enhancing the SMAD-driven promoter activity (Hsu et al., 2009).
T89 12638-12854 Sentence denotes Transforming growth factor β1 binds Hyal-2 as a cognate receptor to signal the formation of the WWOX/Hyal-2/Smad4 complex to relocate to the nucleus for enhancing the SMAD-driven promoter activity (Hsu et al., 2009).
T90 12856-12873 Sentence denotes p53 and Functions
T6773 12874-12989 Sentence denotes Activated p53 mediates apoptosis, cell cycle arrest, senescence, DNA repair, or metabolism (Lane and Levine, 2010).
T91 12874-12989 Sentence denotes Activated p53 mediates apoptosis, cell cycle arrest, senescence, DNA repair, or metabolism (Lane and Levine, 2010).
T6774 12990-13519 Sentence denotes The primary structures of p53 and its isoforms are depicted (Figure 2). p53 induces cell cycle arrest by transactivating genes such as cyclin-dependent kinase inhibitor p21, or microRNA miR34. p53 induces apoptosis by transactivating proapoptotic genes such as BAX, PUMA, SCOTIN, and FAS, and inhibiting the antiapoptotic gene BCL-2 (Lane and Levine, 2010). p53 triggers pro-survival or cell death response, depending upon cell types, the intensity of the stress signal, and the extent of cellular damage (Menendez et al., 2009).
T92 12990-13519 Sentence denotes The primary structures of p53 and its isoforms are depicted (Figure 2). p53 induces cell cycle arrest by transactivating genes such as cyclin-dependent kinase inhibitor p21, or microRNA miR34. p53 induces apoptosis by transactivating proapoptotic genes such as BAX, PUMA, SCOTIN, and FAS, and inhibiting the antiapoptotic gene BCL-2 (Lane and Levine, 2010). p53 triggers pro-survival or cell death response, depending upon cell types, the intensity of the stress signal, and the extent of cellular damage (Menendez et al., 2009).
T6775 13520-13709 Sentence denotes Also, p53 plays a role in controlling cell motility via regulating the expression of smooth muscle α-actin (Comer et al., 1998), collagens IIα1 and VIα1 (Sun et al., 1999), and many others.
T93 13520-13709 Sentence denotes Also, p53 plays a role in controlling cell motility via regulating the expression of smooth muscle α-actin (Comer et al., 1998), collagens IIα1 and VIα1 (Sun et al., 1999), and many others.
T94 13710-13999 Sentence denotes Figure 2 p53 and WWOX in GBM cell apoptosis. (A) Full-length p53 possesses two N-terminal transactivation acidic domains, a proline-rich domain, a central DNA-binding region, and a C-terminal domain, containing a nuclear localization signal, an oligomerization domain, and a basic region.
T14072 13720-13999 Sentence denotes p53 and WWOX in GBM cell apoptosis. (A) Full-length p53 possesses two N-terminal transactivation acidic domains, a proline-rich domain, a central DNA-binding region, and a C-terminal domain, containing a nuclear localization signal, an oligomerization domain, and a basic region.
T14073 14000-14135 Sentence denotes N-terminal deletion mutants of p53 are also shown. (B) Three likely scenarios are proposed for WWOX and p53 to regulate GBM cell death.
T95 14000-14135 Sentence denotes N-terminal deletion mutants of p53 are also shown. (B) Three likely scenarios are proposed for WWOX and p53 to regulate GBM cell death.
T14074 14136-14231 Sentence denotes First, ectopic WWOX fails to induce apoptosis of GBM cells expressing endogenous wild type p53.
T96 14136-14231 Sentence denotes First, ectopic WWOX fails to induce apoptosis of GBM cells expressing endogenous wild type p53.
T14075 14232-14371 Sentence denotes It appears that ectopic WWOX binds and functionally antagonizes p53, and both proteins nullify each other’s function in inducing apoptosis.
T97 14232-14371 Sentence denotes It appears that ectopic WWOX binds and functionally antagonizes p53, and both proteins nullify each other’s function in inducing apoptosis.
T14076 14372-14468 Sentence denotes Second, no physical interactions between mutant p53 proteins and WWOX are expected in GBM cells.
T98 14372-14468 Sentence denotes Second, no physical interactions between mutant p53 proteins and WWOX are expected in GBM cells.
T14077 14469-14536 Sentence denotes Thus, ectopic WWOX induce apoptosis in mutant p53-expressing cells.
T99 14469-14536 Sentence denotes Thus, ectopic WWOX induce apoptosis in mutant p53-expressing cells.
T14078 14537-14589 Sentence denotes Finally, whether WWOX binds p53 isoforms is unknown.
T100 14537-14589 Sentence denotes Finally, whether WWOX binds p53 isoforms is unknown.
T14079 14590-14703 Sentence denotes Also, whether ectopic WWOX induction of apoptosis in GBM cells expressing p53 isoforms remains to be established.
T101 14590-14703 Sentence denotes Also, whether ectopic WWOX induction of apoptosis in GBM cells expressing p53 isoforms remains to be established.
T14080 14704-14833 Sentence denotes TAD, transactivation domain; PrD, proline domain; NLS, nuclear localization signal; OD, oligomerization domain; BR, basic region.
T102 14704-14833 Sentence denotes TAD, transactivation domain; PrD, proline domain; NLS, nuclear localization signal; OD, oligomerization domain; BR, basic region.
T103 14835-14847 Sentence denotes p53 Isoforms
T7491 14848-15055 Sentence denotes At least nine isoforms of p53 have been identified due to alternative mRNA splicing, multiple gene promoters, and alternative initiation sites of translation (Ghosh et al., 2004; Ray et al., 2006; Figure 2).
T104 14848-15055 Sentence denotes At least nine isoforms of p53 have been identified due to alternative mRNA splicing, multiple gene promoters, and alternative initiation sites of translation (Ghosh et al., 2004; Ray et al., 2006; Figure 2).
T7492 15056-15160 Sentence denotes In cancers, aberrant expression of p53 isoforms occurs frequently (Bourdon et al., 2005; Bourdon, 2007).
T105 15056-15160 Sentence denotes In cancers, aberrant expression of p53 isoforms occurs frequently (Bourdon et al., 2005; Bourdon, 2007).
T7493 15161-15396 Sentence denotes Full-length p53, Δ133p53, and p53β are localized mainly in the nucleus, and only few of them are in cytoplasm. p53γ and Δ133p53β are localized in the nucleus and cytoplasm. Δ133p53γ is localized in the cytoplasm (Bourdon et al., 2005).
T106 15161-15396 Sentence denotes Full-length p53, Δ133p53, and p53β are localized mainly in the nucleus, and only few of them are in cytoplasm. p53γ and Δ133p53β are localized in the nucleus and cytoplasm. Δ133p53γ is localized in the cytoplasm (Bourdon et al., 2005).
T7494 15397-15677 Sentence denotes Co-transfection of p53 and p53β increases p53-mediated apoptosis, whereas co-expression of p53 with Δ133p53 suppresses p53-mediated apoptosis (Bourdon et al., 2005). Δ133p53 differentially regulates gene expression in p53-dependent and -independent manners (Aoubala et al., 2011).
T107 15397-15677 Sentence denotes Co-transfection of p53 and p53β increases p53-mediated apoptosis, whereas co-expression of p53 with Δ133p53 suppresses p53-mediated apoptosis (Bourdon et al., 2005). Δ133p53 differentially regulates gene expression in p53-dependent and -independent manners (Aoubala et al., 2011).
T7495 15678-15817 Sentence denotes Co-expression of Δ133p53β or Δ133p53γ with p53 does not affect p53 transcriptional activity on p21 and Bax promoters, as well as apoptosis.
T108 15678-15817 Sentence denotes Co-expression of Δ133p53β or Δ133p53γ with p53 does not affect p53 transcriptional activity on p21 and Bax promoters, as well as apoptosis.
T109 15819-15851 Sentence denotes p53 and WWOX Alterations in GBMs
T8397 15852-16063 Sentence denotes p53 mutants are considered as unfavorable factors for the effectiveness in radiotherapy and TMZ treatment in glioma cells (Gjerset et al., 1995; Hirose et al., 2001; Squatrito et al., 2010; Blough et al., 2011).
T110 15852-16063 Sentence denotes p53 mutants are considered as unfavorable factors for the effectiveness in radiotherapy and TMZ treatment in glioma cells (Gjerset et al., 1995; Hirose et al., 2001; Squatrito et al., 2010; Blough et al., 2011).
T8398 16064-16273 Sentence denotes Loss of functional p53 confers sensitivity to TMZ in glioma cells, whereas wild type p53 increases the TMZ resistance (Blough et al., 2011). p53 mutants reduce TMZ sensitivity in gliomas (Blough et al., 2011).
T111 16064-16273 Sentence denotes Loss of functional p53 confers sensitivity to TMZ in glioma cells, whereas wild type p53 increases the TMZ resistance (Blough et al., 2011). p53 mutants reduce TMZ sensitivity in gliomas (Blough et al., 2011).
T8399 16274-16436 Sentence denotes Altered WWOX expression is shown in GBMs, in which downregulation of WWOX is associated with loss of heterozygosity and promoter methylation (Kosla et al., 2011).
T112 16274-16436 Sentence denotes Altered WWOX expression is shown in GBMs, in which downregulation of WWOX is associated with loss of heterozygosity and promoter methylation (Kosla et al., 2011).
T8400 16437-16622 Sentence denotes Recently, we demonstrated that overexpressed WWOX induces apoptosis of glioblastoma U373-MG cells harboring mutant p53 by causing hypoploidy and DNA fragmentation (Chiang et al., 2012).
T113 16437-16622 Sentence denotes Recently, we demonstrated that overexpressed WWOX induces apoptosis of glioblastoma U373-MG cells harboring mutant p53 by causing hypoploidy and DNA fragmentation (Chiang et al., 2012).
T8401 16623-16696 Sentence denotes However, ectopic WWOX has no effect with U87-MG expressing wild type p53.
T114 16623-16696 Sentence denotes However, ectopic WWOX has no effect with U87-MG expressing wild type p53.
T8402 16697-16836 Sentence denotes Unlike TMZ, WWOX induces apoptosis of U373-MG cells via a mitochondria-independent and caspase-3-independent pathway (Chiang et al., 2012).
T115 16697-16836 Sentence denotes Unlike TMZ, WWOX induces apoptosis of U373-MG cells via a mitochondria-independent and caspase-3-independent pathway (Chiang et al., 2012).
T8403 16837-17034 Sentence denotes While the underlying mechanisms are unknown, it is reasonable to assume that the survival of human glioblastoma cells depends upon interactions between the gain-of-function of p53 mutants and WWOX.
T116 16837-17034 Sentence denotes While the underlying mechanisms are unknown, it is reasonable to assume that the survival of human glioblastoma cells depends upon interactions between the gain-of-function of p53 mutants and WWOX.
T8404 17035-17119 Sentence denotes Activated WWOX binds wild type p53 with Ser46 phosphorylation (Chang et al., 2005b).
T117 17035-17119 Sentence denotes Activated WWOX binds wild type p53 with Ser46 phosphorylation (Chang et al., 2005b).
T8405 17120-17169 Sentence denotes UV irradiation enhances the binding interactions.
T118 17120-17169 Sentence denotes UV irradiation enhances the binding interactions.
T8406 17170-17270 Sentence denotes Despite the presence of Ser46 in Δ40p53, binding of this protein with WWOX remains to be determined.
T119 17170-17270 Sentence denotes Despite the presence of Ser46 in Δ40p53, binding of this protein with WWOX remains to be determined.
T8407 17271-17462 Sentence denotes We postulate that in GBM cells, both wild type p53 and ectopic WWOX proteins appear to have a functional antagonism, thereby nullifying each other’s function in inducing apoptosis (Figure 2).
T120 17271-17462 Sentence denotes We postulate that in GBM cells, both wild type p53 and ectopic WWOX proteins appear to have a functional antagonism, thereby nullifying each other’s function in inducing apoptosis (Figure 2).
T8408 17463-17559 Sentence denotes Mutant p53 proteins cannot bind ectopic WWOX in GBM cells, and WWOX is able to induce apoptosis.
T121 17463-17559 Sentence denotes Mutant p53 proteins cannot bind ectopic WWOX in GBM cells, and WWOX is able to induce apoptosis.
T8409 17560-17662 Sentence denotes Whether WWOX causes apoptosis in GBM expressing p53 isoforms is unknown and remains to be established.
T122 17560-17662 Sentence denotes Whether WWOX causes apoptosis in GBM expressing p53 isoforms is unknown and remains to be established.
T123 17664-17676 Sentence denotes Perspectives
T9743 17677-17740 Sentence denotes Whether WWOX affects TMZ sensitivity has never been determined.
T124 17677-17740 Sentence denotes Whether WWOX affects TMZ sensitivity has never been determined.
T9744 17741-17842 Sentence denotes Binding proteins for WWOX and/or p53 are likely to affect apoptosis and TMZ sensitivity in GBM cells.
T125 17741-17842 Sentence denotes Binding proteins for WWOX and/or p53 are likely to affect apoptosis and TMZ sensitivity in GBM cells.
T9745 17843-17958 Sentence denotes WWOX binds MEK, and that PMA dissociates this complex for causing apoptosis of T leukemia cells (Lin et al., 2011).
T126 17843-17958 Sentence denotes WWOX binds MEK, and that PMA dissociates this complex for causing apoptosis of T leukemia cells (Lin et al., 2011).
T9746 17959-18065 Sentence denotes Thus, appropriate chemicals, which break apart the WWOX/MEK complex, are expected to cause GBM cell death.
T127 17959-18065 Sentence denotes Thus, appropriate chemicals, which break apart the WWOX/MEK complex, are expected to cause GBM cell death.
T9747 18066-18233 Sentence denotes Preliminary studies from our screening of chemicals have selected certain small molecules that induce apoptosis of many types of cancer cells (Lu et al., unpublished).
T128 18066-18233 Sentence denotes Preliminary studies from our screening of chemicals have selected certain small molecules that induce apoptosis of many types of cancer cells (Lu et al., unpublished).
T9748 18234-18351 Sentence denotes Indeed, specific inhibition of MEK by selumetinib enhances TMZ-induced cancer cell death in vivo (Holt et al., 2012).
T129 18234-18351 Sentence denotes Indeed, specific inhibition of MEK by selumetinib enhances TMZ-induced cancer cell death in vivo (Holt et al., 2012).
T9749 18352-18409 Sentence denotes Serum factors can be utilized for blocking cancer growth.
T130 18352-18409 Sentence denotes Serum factors can be utilized for blocking cancer growth.
T9750 18410-18607 Sentence denotes For example, serum complement C1q induces apoptosis of prostate cancer and neuroblastomas cells without participation of downstream proteins in the classical activation pathway (Hong et al., 2009).
T131 18410-18607 Sentence denotes For example, serum complement C1q induces apoptosis of prostate cancer and neuroblastomas cells without participation of downstream proteins in the classical activation pathway (Hong et al., 2009).
T9751 18608-18672 Sentence denotes In this event, ectopic WWOX is activated for inducing apoptosis.
T132 18608-18672 Sentence denotes In this event, ectopic WWOX is activated for inducing apoptosis.
T9752 18673-18793 Sentence denotes Failure of ectopic WWOX in inducing apoptosis of glioma cells possessing wild type p53 is unusual (Chiang et al., 2012).
T133 18673-18793 Sentence denotes Failure of ectopic WWOX in inducing apoptosis of glioma cells possessing wild type p53 is unusual (Chiang et al., 2012).
T9753 18794-18996 Sentence denotes In most cases, we have shown that p53 functionally interacts with WWOX, and both proteins induce apoptosis in a synergistic manner (Chang et al., 2001, 2003, 2005a,b, 2007, 2010, 2012; Su et al., 2012).
T134 18794-18996 Sentence denotes In most cases, we have shown that p53 functionally interacts with WWOX, and both proteins induce apoptosis in a synergistic manner (Chang et al., 2001, 2003, 2005a,b, 2007, 2010, 2012; Su et al., 2012).
T9754 18997-19130 Sentence denotes A likely scenario is that p53-binding proteins, which are present in GBMs, may interfere with the apoptotic function of WWOX and p53.
T135 18997-19130 Sentence denotes A likely scenario is that p53-binding proteins, which are present in GBMs, may interfere with the apoptotic function of WWOX and p53.
T9755 19131-19221 Sentence denotes Functional antagonism among tumor suppressors has never been documented in the literature.
T136 19131-19221 Sentence denotes Functional antagonism among tumor suppressors has never been documented in the literature.
T9756 19222-19464 Sentence denotes However, it is not surprising to find that many tumor suppressor proteins, e.g., p53, WWOX, Smad4, PTEN, PP2A, and etc., are significantly upregulated during the early stage of cancer progression (Lai et al., 2005; Chang et al., unpublished).
T137 19222-19464 Sentence denotes However, it is not surprising to find that many tumor suppressor proteins, e.g., p53, WWOX, Smad4, PTEN, PP2A, and etc., are significantly upregulated during the early stage of cancer progression (Lai et al., 2005; Chang et al., unpublished).
T9757 19465-19562 Sentence denotes Do these proteins act synergistically in blocking cancer progression but lose control eventually?
T138 19465-19562 Sentence denotes Do these proteins act synergistically in blocking cancer progression but lose control eventually?
T9758 19563-19637 Sentence denotes Or, do they counteract each other’s function, thus allowing cancer growth?
T139 19563-19637 Sentence denotes Or, do they counteract each other’s function, thus allowing cancer growth?
T9759 19638-19751 Sentence denotes Whether endogenous WWOX counteracts with the function of endogenous p53 is unknown and remains to be established.
T140 19638-19751 Sentence denotes Whether endogenous WWOX counteracts with the function of endogenous p53 is unknown and remains to be established.
T9760 19752-19864 Sentence denotes One of the unique characteristics for malignant gliomas is their diffuse infiltration into distant brain tissue.
T141 19752-19864 Sentence denotes One of the unique characteristics for malignant gliomas is their diffuse infiltration into distant brain tissue.
T9761 19865-20028 Sentence denotes Signal pathways, involving PI3K, Akt, mTOR, NF-κB, and autophagy, are believed to confer these migrating cells resistant to apoptotic death (Lefranc et al., 2005).
T142 19865-20028 Sentence denotes Signal pathways, involving PI3K, Akt, mTOR, NF-κB, and autophagy, are believed to confer these migrating cells resistant to apoptotic death (Lefranc et al., 2005).
T9762 20029-20305 Sentence denotes Glioma cells possess CD44 as a receptor for interacting with brain matrix hyaluronan (Murai et al., 2004; Yoshida et al., 2012), and secrete hyaluronidases and metalloproteinases to facilitate their migration (Delpech et al., 2002; Junker et al., 2003; Hagemann et al., 2012).
T143 20029-20305 Sentence denotes Glioma cells possess CD44 as a receptor for interacting with brain matrix hyaluronan (Murai et al., 2004; Yoshida et al., 2012), and secrete hyaluronidases and metalloproteinases to facilitate their migration (Delpech et al., 2002; Junker et al., 2003; Hagemann et al., 2012).
T9763 20306-20374 Sentence denotes Also, lack of WWOX expression is expected to enhance cell migration.
T144 20306-20374 Sentence denotes Also, lack of WWOX expression is expected to enhance cell migration.
T9764 20375-20510 Sentence denotes For example, loss of WWOX facilitates migration of ovarian cancer and osteosarcoma cells (Gourley et al., 2009; Del Mare et al., 2011).
T145 20375-20510 Sentence denotes For example, loss of WWOX facilitates migration of ovarian cancer and osteosarcoma cells (Gourley et al., 2009; Del Mare et al., 2011).
T9765 20511-20708 Sentence denotes Ectopic expression of TIAF1 (TGF-β-induced antiapoptotic factor), p53, and WWOX suppresses anchorage-independent growth and cell migration and causes apoptosis in cancer cells (Chang et al., 2012).
T146 20511-20708 Sentence denotes Ectopic expression of TIAF1 (TGF-β-induced antiapoptotic factor), p53, and WWOX suppresses anchorage-independent growth and cell migration and causes apoptosis in cancer cells (Chang et al., 2012).
T9766 20709-20817 Sentence denotes We believe that glioma cells, with stem cell-like properties, migrate individually rather than collectively.
T147 20709-20817 Sentence denotes We believe that glioma cells, with stem cell-like properties, migrate individually rather than collectively.
T9767 20818-20969 Sentence denotes This assumption is based upon our observations that mouse Wwox gene knockout cells (e.g., embryonic fibroblasts) migrate individually and aggressively.
T148 20818-20969 Sentence denotes This assumption is based upon our observations that mouse Wwox gene knockout cells (e.g., embryonic fibroblasts) migrate individually and aggressively.
T9768 20970-21047 Sentence denotes In contrast, wild type cells migrate collectively (Chou et al., unpublished).
T149 20970-21047 Sentence denotes In contrast, wild type cells migrate collectively (Chou et al., unpublished).
T9769 21048-21286 Sentence denotes While a portion of WWOX is anchored on the cell membrane/cytoskeleton, WWOX-negative cells lose recognition by parental WWOX-positive cells, and this increases the mobility of WWOX-negative cells to move away from the WWOX-positive cells.
T150 21048-21286 Sentence denotes While a portion of WWOX is anchored on the cell membrane/cytoskeleton, WWOX-negative cells lose recognition by parental WWOX-positive cells, and this increases the mobility of WWOX-negative cells to move away from the WWOX-positive cells.
T9770 21287-21424 Sentence denotes Conceivably, WWOX-negative glioma cells migrate individually and turn away from WWOX-expressing brain cells to low WWOX expression areas.
T151 21287-21424 Sentence denotes Conceivably, WWOX-negative glioma cells migrate individually and turn away from WWOX-expressing brain cells to low WWOX expression areas.
T9771 21425-21580 Sentence denotes Apparently, the migratory behavior of WWOX-negative glioma cells may account for the diffuse invasion into distant brain tissue (Chou et al., unpublished).
T152 21425-21580 Sentence denotes Apparently, the migratory behavior of WWOX-negative glioma cells may account for the diffuse invasion into distant brain tissue (Chou et al., unpublished).
T9772 21581-21799 Sentence denotes Metabolic alterations have been shown in Wwox knockout mice, including postnatal lethality, bone metabolism defects, ataxia, steroidogenesis, and generation of osteosarcomas (Del Mare et al., 2011; Salah et al., 2012).
T153 21581-21799 Sentence denotes Metabolic alterations have been shown in Wwox knockout mice, including postnatal lethality, bone metabolism defects, ataxia, steroidogenesis, and generation of osteosarcomas (Del Mare et al., 2011; Salah et al., 2012).
T9773 21800-21959 Sentence denotes In a Drosophila model, Wwox is shown to participate in pathways involving aerobic metabolism and oxidative stress for generation of ROS (O’Keefe et al., 2011).
T154 21800-21959 Sentence denotes In a Drosophila model, Wwox is shown to participate in pathways involving aerobic metabolism and oxidative stress for generation of ROS (O’Keefe et al., 2011).
T155 21960-22046 Sentence denotes Under UV stress, functional Wwox gene expression induces ROS production in Drosophila.
T9774 21960-22167 Sentence denotes Under UV stress, functional Wwox gene expression induces ROS production in Drosophila. Cancer cells are known to overly utilize glycolysis for growth advantage – the so-called Warburg (Moncada et al., 2012).
T156 22047-22167 Sentence denotes Cancer cells are known to overly utilize glycolysis for growth advantage – the so-called Warburg (Moncada et al., 2012).
T9775 22168-22317 Sentence denotes Conceivably, WWOX is likely to override glucose consumption in cancer cells and exerts generation of ROS to curb the cancer cell growth and invasion.
T157 22168-22317 Sentence denotes Conceivably, WWOX is likely to override glucose consumption in cancer cells and exerts generation of ROS to curb the cancer cell growth and invasion.
T9776 22318-22472 Sentence denotes In summary, in this perspective article we have discussed the potential role of tumor suppressors p53 and WWOX in regulating TMZ sensitivity in GBM cells.
T158 22318-22472 Sentence denotes In summary, in this perspective article we have discussed the potential role of tumor suppressors p53 and WWOX in regulating TMZ sensitivity in GBM cells.
T9777 22473-22641 Sentence denotes We have shown the role of WWOX in controlling cell migration and metabolic alterations, and discussed the effects of WWOX deficiency and TMZ resistance in cancer cells.
T159 22473-22641 Sentence denotes We have shown the role of WWOX in controlling cell migration and metabolic alterations, and discussed the effects of WWOX deficiency and TMZ resistance in cancer cells.
T160 22643-22663 Sentence denotes Authors Contribution
T12465 22664-22945 Sentence denotes Ming-Fu Chiang and Chun-I Sze wrote the sections dealing with TMZ; Pei-Yi Chou wrote the review sections for p53 and WWOX and designed graphs; Wan-Jen Wang managed citations; Nan-Shan Chang conceived ideas, wrote and thoroughly revised the manuscript, and discussed with coauthors.
T161 22664-22945 Sentence denotes Ming-Fu Chiang and Chun-I Sze wrote the sections dealing with TMZ; Pei-Yi Chou wrote the review sections for p53 and WWOX and designed graphs; Wan-Jen Wang managed citations; Nan-Shan Chang conceived ideas, wrote and thoroughly revised the manuscript, and discussed with coauthors.
T162 22947-22977 Sentence denotes Conflict of Interest Statement
T12590 22978-23150 Sentence denotes The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
T163 22978-23150 Sentence denotes The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.