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Id Subject Object Predicate Lexical cue
T10 0-57 Sentence denotes Mechanisms of Resistance to Temozolomide in Glioblastomas
T875 58-197 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 58-197 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 198-389 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 198-389 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 390-543 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 390-543 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 544-750 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 544-750 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 751-1141 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 751-1141 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 1142-1302 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 1142-1302 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 1303-1428 Sentence denotes The O6-methylguanine lesion is known to trigger autophagy, rather than apoptosis, to cause cell death (Kanzawa et al., 2003).
T17 1303-1428 Sentence denotes The O6-methylguanine lesion is known to trigger autophagy, rather than apoptosis, to cause cell death (Kanzawa et al., 2003).
T882 1429-1595 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 1429-1595 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 1596-1751 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 1596-1751 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 1752-1866 Sentence denotes Also, MAPO2 (C1orf201) gene participates in the O6-methylguanine lesion-induced apoptosis (Fujikane et al., 2012).
T20 1752-1866 Sentence denotes Also, MAPO2 (C1orf201) gene participates in the O6-methylguanine lesion-induced apoptosis (Fujikane et al., 2012).
T885 1867-1909 Sentence denotes MAPO2 gene encodes a novel 37-kDa protein.
T21 1867-1909 Sentence denotes MAPO2 gene encodes a novel 37-kDa protein.
T886 1910-1974 Sentence denotes It is not determined whether this gene is involved in autophagy.
T22 1910-1974 Sentence denotes It is not determined whether this gene is involved in autophagy.
T887 1975-2172 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 1975-2172 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 2173-2421 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 2173-2421 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 2422-2593 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 2422-2593 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 2594-2671 Sentence denotes The initiation of apoptotic signaling fails in the absence of the MMR system.
T26 2594-2671 Sentence denotes The initiation of apoptotic signaling fails in the absence of the MMR system.
T891 2672-2831 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 2672-2831 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 2832-2950 Sentence denotes An increase in MGMT gene promoter methylation, which blocks MGMT protein expression, prolongs cancer patient survival.
T28 2832-2950 Sentence denotes An increase in MGMT gene promoter methylation, which blocks MGMT protein expression, prolongs cancer patient survival.
T893 2951-3097 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 2951-3097 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 3098-3184 Sentence denotes MicroRNA-21 is considered as a pro-survival factor for cancer cells (Li et al., 2012).
T30 3098-3184 Sentence denotes MicroRNA-21 is considered as a pro-survival factor for cancer cells (Li et al., 2012).
T895 3185-3488 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 3185-3488 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 3489-3699 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 3489-3699 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 3700-3921 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 3700-3921 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 3922-4073 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 3922-4073 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 4074-4279 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 4074-4279 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 4280-4439 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 4280-4439 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 4440-4624 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 4440-4624 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 4625-4738 Sentence denotes Resveratrol, a natural polyphenol, reverses TMZ resistance via an NF-κB-dependent mechanism (Huang et al., 2012).
T38 4625-4738 Sentence denotes Resveratrol, a natural polyphenol, reverses TMZ resistance via an NF-κB-dependent mechanism (Huang et al., 2012).
T903 4739-4850 Sentence denotes STAT3 inhibitor or STAT3 knockdown potentiates TMZ efficacy in resistant GBM cell lines (Kohsaka et al., 2012).
T39 4739-4850 Sentence denotes STAT3 inhibitor or STAT3 knockdown potentiates TMZ efficacy in resistant GBM cell lines (Kohsaka et al., 2012).
T904 4851-4951 Sentence denotes Intratumoral hypoxia is common in GBMs and may be associated with the development of TMZ resistance.
T40 4851-4951 Sentence denotes Intratumoral hypoxia is common in GBMs and may be associated with the development of TMZ resistance.
T905 4952-5039 Sentence denotes Induced hyperoxia can be utilized to reverse TMZ resistance in GBMs (Sun et al., 2012).
T41 4952-5039 Sentence denotes Induced hyperoxia can be utilized to reverse TMZ resistance in GBMs (Sun et al., 2012).
T906 5040-5107 Sentence denotes Cancer stem cells are probably the key to failure in TMZ treatment.
T42 5040-5107 Sentence denotes Cancer stem cells are probably the key to failure in TMZ treatment.
T907 5108-5296 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 5108-5296 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 5297-5423 Sentence denotes CD133-positive cancer stem cells are expressed in both normal stem cells and cancer stem cells (Donovan and Pilkington, 2012).
T44 5297-5423 Sentence denotes CD133-positive cancer stem cells are expressed in both normal stem cells and cancer stem cells (Donovan and Pilkington, 2012).
T909 5424-5554 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 5424-5554 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 5556-5596 Sentence denotes WW Domain-Containing Oxidoreductase WWOX
T3823 5597-5719 Sentence denotes Recently, tumor suppressors p53 and WWOX were shown to regulate the apoptosis of glioblastoma cells (Chiang et al., 2012).
T47 5597-5719 Sentence denotes Recently, tumor suppressors p53 and WWOX were shown to regulate the apoptosis of glioblastoma cells (Chiang et al., 2012).
T3824 5720-5830 Sentence denotes WW domain-containing oxidoreductase, known as WWOX, FOR, or WOX1, is encoded by human or mouse WWOX/Wwox gene.
T48 5720-5830 Sentence denotes WW domain-containing oxidoreductase, known as WWOX, FOR, or WOX1, is encoded by human or mouse WWOX/Wwox gene.
T3825 5831-5928 Sentence denotes This gene is located in chromosome 16q23.3–24.1, an area known as the common fragile site FRA16D.
T49 5831-5928 Sentence denotes This gene is located in chromosome 16q23.3–24.1, an area known as the common fragile site FRA16D.
T3826 5929-6220 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 5929-6220 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 6221-6421 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 6221-6421 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 6422-6495 Sentence denotes Figure 1 Schematic diagrams of WWOX structure and its role in signaling.
T12775 6432-6495 Sentence denotes Schematic diagrams of WWOX structure and its role in signaling.
T12776 6496-6624 Sentence denotes WWOX contains two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region.
T53 6496-6624 Sentence denotes WWOX contains two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region.
T12777 6625-6786 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 6625-6786 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 6787-6842 Sentence denotes The SDR domain possesses a mitochondria-binding region.
T55 6787-6842 Sentence denotes The SDR domain possesses a mitochondria-binding region.
T12779 6843-6916 Sentence denotes There are two conserved tyrosine phosphorylation sites, Tyr33 and Tyr287.
T56 6843-6916 Sentence denotes There are two conserved tyrosine phosphorylation sites, Tyr33 and Tyr287.
T12780 6917-7041 Sentence denotes Other phosphorylation sites predicted by NetPhos 2.0 Server are Tyr6, Thr12, Ser14, Tyr61, Tyr293, and Thr3B3, respectively.
T57 6917-7041 Sentence denotes Other phosphorylation sites predicted by NetPhos 2.0 Server are Tyr6, Thr12, Ser14, Tyr61, Tyr293, and Thr3B3, respectively.
T12781 7042-7113 Sentence denotes Upon stress stimulation, WWOX is phosphorylated in Tyr33 and binds p53.
T58 7042-7113 Sentence denotes Upon stress stimulation, WWOX is phosphorylated in Tyr33 and binds p53.
T12782 7114-7200 Sentence denotes The WWOX/p53 complex then translocates to mitochondria or nucleus to induce apoptosis.
T59 7114-7200 Sentence denotes The WWOX/p53 complex then translocates to mitochondria or nucleus to induce apoptosis.
T12783 7201-7409 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 7201-7409 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 7410-7444 Sentence denotes WWOX binds Tau via its SDR domain.
T61 7410-7444 Sentence denotes WWOX binds Tau via its SDR domain.
T12785 7445-7548 Sentence denotes WWOX participates in the Wnt/β-catenin signal pathway by binding Dvl and inhibiting its nuclear import.
T62 7445-7548 Sentence denotes WWOX participates in the Wnt/β-catenin signal pathway by binding Dvl and inhibiting its nuclear import.
T12786 7549-7707 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 7549-7707 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 7708-7792 Sentence denotes WWOX is recruited to the membrane area by association with Hyal-2 and phospho-Ezrin.
T12787 7708-7838 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 7793-7838 Sentence denotes Hyal-2 is an alternative receptor for TGF-β1.
T12788 7839-7987 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 7839-7987 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 7988-8140 Sentence denotes Ack1, activated Cdc42-associated kinase 1; Hyal-2, hyaluronoglucosaminidase 2; CKI, casein kinase; GSK, glycogen synthase kinase; PKA, protein kinase A.
T67 7988-8140 Sentence denotes Ack1, activated Cdc42-associated kinase 1; Hyal-2, hyaluronoglucosaminidase 2; CKI, casein kinase; GSK, glycogen synthase kinase; PKA, protein kinase A.
T3828 8141-8558 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 8141-8558 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 8559-8725 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 8559-8725 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 8726-8948 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 8726-8948 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 8949-9133 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 8949-9133 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 9134-9305 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 9134-9305 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 9306-9395 Sentence denotes No blocking of translocation of transcription factors to the nuclei by Wwox was observed.
T73 9306-9395 Sentence denotes No blocking of translocation of transcription factors to the nuclei by Wwox was observed.
T3834 9396-9568 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 9396-9568 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 9569-9721 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 9569-9721 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 9722-9837 Sentence denotes Also, WWOX binds Disheveled proteins (Dvl), which are key components in Wnt/β-catenin signaling pathway (Figure 1).
T76 9722-9837 Sentence denotes Also, WWOX binds Disheveled proteins (Dvl), which are key components in Wnt/β-catenin signaling pathway (Figure 1).
T77 9838-9862 Sentence denotes No PPxY motif is in Dvl.
T3837 9838-10016 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 9863-10016 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 10017-10223 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 10017-10223 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 10224-10395 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 10224-10395 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 10396-10452 Sentence denotes Also, WWOX mediates cell death synergistically with p53.
T81 10396-10452 Sentence denotes Also, WWOX mediates cell death synergistically with p53.
T3841 10453-10722 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 10453-10722 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 10723-10775 Sentence denotes WWOX binds MEK in Jurkat T cells (Lin et al., 2011).
T83 10723-10775 Sentence denotes WWOX binds MEK in Jurkat T cells (Lin et al., 2011).
T3843 10776-10954 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 10776-10954 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 10955-11058 Sentence denotes Inhibition of MEK activity increases TMZ-induced suppression of cancer cell growth (Holt et al., 2012).
T85 10955-11058 Sentence denotes Inhibition of MEK activity increases TMZ-induced suppression of cancer cell growth (Holt et al., 2012).
T3845 11059-11228 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 11059-11228 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 11229-11399 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 11229-11399 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 11400-11558 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 11400-11558 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 11559-11775 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 11559-11775 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 11777-11794 Sentence denotes p53 and Functions
T6773 11795-11910 Sentence denotes Activated p53 mediates apoptosis, cell cycle arrest, senescence, DNA repair, or metabolism (Lane and Levine, 2010).
T91 11795-11910 Sentence denotes Activated p53 mediates apoptosis, cell cycle arrest, senescence, DNA repair, or metabolism (Lane and Levine, 2010).
T6774 11911-12440 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 11911-12440 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 12441-12630 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 12441-12630 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 12631-12920 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 12641-12920 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 12921-13056 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 12921-13056 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 13057-13152 Sentence denotes First, ectopic WWOX fails to induce apoptosis of GBM cells expressing endogenous wild type p53.
T96 13057-13152 Sentence denotes First, ectopic WWOX fails to induce apoptosis of GBM cells expressing endogenous wild type p53.
T14075 13153-13292 Sentence denotes It appears that ectopic WWOX binds and functionally antagonizes p53, and both proteins nullify each other’s function in inducing apoptosis.
T97 13153-13292 Sentence denotes It appears that ectopic WWOX binds and functionally antagonizes p53, and both proteins nullify each other’s function in inducing apoptosis.
T14076 13293-13389 Sentence denotes Second, no physical interactions between mutant p53 proteins and WWOX are expected in GBM cells.
T98 13293-13389 Sentence denotes Second, no physical interactions between mutant p53 proteins and WWOX are expected in GBM cells.
T14077 13390-13457 Sentence denotes Thus, ectopic WWOX induce apoptosis in mutant p53-expressing cells.
T99 13390-13457 Sentence denotes Thus, ectopic WWOX induce apoptosis in mutant p53-expressing cells.
T14078 13458-13510 Sentence denotes Finally, whether WWOX binds p53 isoforms is unknown.
T100 13458-13510 Sentence denotes Finally, whether WWOX binds p53 isoforms is unknown.
T14079 13511-13624 Sentence denotes Also, whether ectopic WWOX induction of apoptosis in GBM cells expressing p53 isoforms remains to be established.
T101 13511-13624 Sentence denotes Also, whether ectopic WWOX induction of apoptosis in GBM cells expressing p53 isoforms remains to be established.
T14080 13625-13754 Sentence denotes TAD, transactivation domain; PrD, proline domain; NLS, nuclear localization signal; OD, oligomerization domain; BR, basic region.
T102 13625-13754 Sentence denotes TAD, transactivation domain; PrD, proline domain; NLS, nuclear localization signal; OD, oligomerization domain; BR, basic region.
T103 13756-13768 Sentence denotes p53 Isoforms
T7491 13769-13976 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 13769-13976 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 13977-14081 Sentence denotes In cancers, aberrant expression of p53 isoforms occurs frequently (Bourdon et al., 2005; Bourdon, 2007).
T105 13977-14081 Sentence denotes In cancers, aberrant expression of p53 isoforms occurs frequently (Bourdon et al., 2005; Bourdon, 2007).
T7493 14082-14317 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 14082-14317 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 14318-14598 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 14318-14598 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 14599-14738 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 14599-14738 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 14740-14772 Sentence denotes p53 and WWOX Alterations in GBMs
T8397 14773-14984 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 14773-14984 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 14985-15194 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 14985-15194 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 15195-15357 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 15195-15357 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 15358-15543 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 15358-15543 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 15544-15617 Sentence denotes However, ectopic WWOX has no effect with U87-MG expressing wild type p53.
T114 15544-15617 Sentence denotes However, ectopic WWOX has no effect with U87-MG expressing wild type p53.
T8402 15618-15757 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 15618-15757 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 15758-15955 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 15758-15955 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 15956-16040 Sentence denotes Activated WWOX binds wild type p53 with Ser46 phosphorylation (Chang et al., 2005b).
T117 15956-16040 Sentence denotes Activated WWOX binds wild type p53 with Ser46 phosphorylation (Chang et al., 2005b).
T8405 16041-16090 Sentence denotes UV irradiation enhances the binding interactions.
T118 16041-16090 Sentence denotes UV irradiation enhances the binding interactions.
T8406 16091-16191 Sentence denotes Despite the presence of Ser46 in Δ40p53, binding of this protein with WWOX remains to be determined.
T119 16091-16191 Sentence denotes Despite the presence of Ser46 in Δ40p53, binding of this protein with WWOX remains to be determined.
T8407 16192-16383 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 16192-16383 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 16384-16480 Sentence denotes Mutant p53 proteins cannot bind ectopic WWOX in GBM cells, and WWOX is able to induce apoptosis.
T121 16384-16480 Sentence denotes Mutant p53 proteins cannot bind ectopic WWOX in GBM cells, and WWOX is able to induce apoptosis.
T8409 16481-16583 Sentence denotes Whether WWOX causes apoptosis in GBM expressing p53 isoforms is unknown and remains to be established.
T122 16481-16583 Sentence denotes Whether WWOX causes apoptosis in GBM expressing p53 isoforms is unknown and remains to be established.
T123 16585-16597 Sentence denotes Perspectives
T9743 16598-16661 Sentence denotes Whether WWOX affects TMZ sensitivity has never been determined.
T124 16598-16661 Sentence denotes Whether WWOX affects TMZ sensitivity has never been determined.
T9744 16662-16763 Sentence denotes Binding proteins for WWOX and/or p53 are likely to affect apoptosis and TMZ sensitivity in GBM cells.
T125 16662-16763 Sentence denotes Binding proteins for WWOX and/or p53 are likely to affect apoptosis and TMZ sensitivity in GBM cells.
T9745 16764-16879 Sentence denotes WWOX binds MEK, and that PMA dissociates this complex for causing apoptosis of T leukemia cells (Lin et al., 2011).
T126 16764-16879 Sentence denotes WWOX binds MEK, and that PMA dissociates this complex for causing apoptosis of T leukemia cells (Lin et al., 2011).
T9746 16880-16986 Sentence denotes Thus, appropriate chemicals, which break apart the WWOX/MEK complex, are expected to cause GBM cell death.
T127 16880-16986 Sentence denotes Thus, appropriate chemicals, which break apart the WWOX/MEK complex, are expected to cause GBM cell death.
T9747 16987-17154 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 16987-17154 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 17155-17272 Sentence denotes Indeed, specific inhibition of MEK by selumetinib enhances TMZ-induced cancer cell death in vivo (Holt et al., 2012).
T129 17155-17272 Sentence denotes Indeed, specific inhibition of MEK by selumetinib enhances TMZ-induced cancer cell death in vivo (Holt et al., 2012).
T9749 17273-17330 Sentence denotes Serum factors can be utilized for blocking cancer growth.
T130 17273-17330 Sentence denotes Serum factors can be utilized for blocking cancer growth.
T9750 17331-17528 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 17331-17528 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 17529-17593 Sentence denotes In this event, ectopic WWOX is activated for inducing apoptosis.
T132 17529-17593 Sentence denotes In this event, ectopic WWOX is activated for inducing apoptosis.
T9752 17594-17714 Sentence denotes Failure of ectopic WWOX in inducing apoptosis of glioma cells possessing wild type p53 is unusual (Chiang et al., 2012).
T133 17594-17714 Sentence denotes Failure of ectopic WWOX in inducing apoptosis of glioma cells possessing wild type p53 is unusual (Chiang et al., 2012).
T9753 17715-17917 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 17715-17917 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 17918-18051 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 17918-18051 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 18052-18142 Sentence denotes Functional antagonism among tumor suppressors has never been documented in the literature.
T136 18052-18142 Sentence denotes Functional antagonism among tumor suppressors has never been documented in the literature.
T9756 18143-18385 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 18143-18385 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 18386-18483 Sentence denotes Do these proteins act synergistically in blocking cancer progression but lose control eventually?
T138 18386-18483 Sentence denotes Do these proteins act synergistically in blocking cancer progression but lose control eventually?
T9758 18484-18558 Sentence denotes Or, do they counteract each other’s function, thus allowing cancer growth?
T139 18484-18558 Sentence denotes Or, do they counteract each other’s function, thus allowing cancer growth?
T9759 18559-18672 Sentence denotes Whether endogenous WWOX counteracts with the function of endogenous p53 is unknown and remains to be established.
T140 18559-18672 Sentence denotes Whether endogenous WWOX counteracts with the function of endogenous p53 is unknown and remains to be established.
T9760 18673-18785 Sentence denotes One of the unique characteristics for malignant gliomas is their diffuse infiltration into distant brain tissue.
T141 18673-18785 Sentence denotes One of the unique characteristics for malignant gliomas is their diffuse infiltration into distant brain tissue.
T9761 18786-18949 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 18786-18949 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 18950-19226 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 18950-19226 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 19227-19295 Sentence denotes Also, lack of WWOX expression is expected to enhance cell migration.
T144 19227-19295 Sentence denotes Also, lack of WWOX expression is expected to enhance cell migration.
T9764 19296-19431 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 19296-19431 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 19432-19629 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 19432-19629 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 19630-19738 Sentence denotes We believe that glioma cells, with stem cell-like properties, migrate individually rather than collectively.
T147 19630-19738 Sentence denotes We believe that glioma cells, with stem cell-like properties, migrate individually rather than collectively.
T9767 19739-19890 Sentence denotes This assumption is based upon our observations that mouse Wwox gene knockout cells (e.g., embryonic fibroblasts) migrate individually and aggressively.
T148 19739-19890 Sentence denotes This assumption is based upon our observations that mouse Wwox gene knockout cells (e.g., embryonic fibroblasts) migrate individually and aggressively.
T9768 19891-19968 Sentence denotes In contrast, wild type cells migrate collectively (Chou et al., unpublished).
T149 19891-19968 Sentence denotes In contrast, wild type cells migrate collectively (Chou et al., unpublished).
T9769 19969-20207 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 19969-20207 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 20208-20345 Sentence denotes Conceivably, WWOX-negative glioma cells migrate individually and turn away from WWOX-expressing brain cells to low WWOX expression areas.
T151 20208-20345 Sentence denotes Conceivably, WWOX-negative glioma cells migrate individually and turn away from WWOX-expressing brain cells to low WWOX expression areas.
T9771 20346-20501 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 20346-20501 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 20502-20720 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 20502-20720 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 20721-20880 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 20721-20880 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 20881-20967 Sentence denotes Under UV stress, functional Wwox gene expression induces ROS production in Drosophila.
T9774 20881-21088 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 20968-21088 Sentence denotes Cancer cells are known to overly utilize glycolysis for growth advantage – the so-called Warburg (Moncada et al., 2012).
T9775 21089-21238 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 21089-21238 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 21239-21393 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 21239-21393 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 21394-21562 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 21394-21562 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 21564-21584 Sentence denotes Authors Contribution
T12465 21585-21866 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 21585-21866 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 21868-21898 Sentence denotes Conflict of Interest Statement
T12590 21899-22071 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 21899-22071 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.