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系統識別號 U0026-3008201316242300
論文名稱(中文) 含雙色胺酸功能區氧化還原酶在壓力反應下的作用
論文名稱(英文) WW domain-containing oxidoreductase in stress responses
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 101
學期 2
出版年 102
研究生(中文) 蘇郁涵
研究生(英文) Yu-Han Su
學號 t36004063
學位類別 碩士
語文別 英文
論文頁數 80頁
口試委員 指導教授-徐麗君
口試委員-張南山
口試委員-詹明修
中文關鍵字 血清缺乏  細胞凋亡  氧化壓力 
英文關鍵字 serum starvation  Bcl-2 family  oxidative stress 
學科別分類
中文摘要 中文摘要
抑癌蛋白質名為含雙色胺酸功能區氧化還原酶 (WW domain-containing oxidoreductase,亦稱作WWOX,FOR或是WOX1) 的基因位於人類染色體上易斷裂 (fragile) 的片段上,在許多的癌症中常可發現WWOX基因的變異。此外,WWOX/Wwox蛋白質的表現情形與癌症的發展進程也呈現高度相關性。然而,何種刺激可調控WWOX/Wwox的表現仍尚未明瞭。由我們的研究中發現,人類鱗狀上皮癌細胞SCC-15在缺乏血清 (serum) 內的生長因子刺激或是在過氧化氫 (H2O2) 及抗癌藥物處理的情況下,其細胞中的WWOX/Wwox基因被大量轉錄,並造成WWOX/Wwox蛋白質大量表現。Wwox+/+小鼠胚胎纖維母細胞 (MEFs) 在血清缺乏或是過氧化氫處理下也可觀察到相同的結果。為了更進一步研究WWOX/Wwox在壓力存在下所扮演的角色,我們分析細胞在血清缺乏時的存活情形,發現Wwox+/+ MEFs在血清缺乏時導致的細胞死亡明顯高於Wwox-/- MEFs。此外,血清缺乏的情況亦造成Wwox+/+ MEFs細胞中的活性氧化物 (ROS) 較Wwox-/- MEFs高。隨著血清缺乏的時間延長,Wwox+/+ MEFs內可調節粒線體內的恆定的抗細胞凋亡蛋白質Bcl-XL及Mcl-1表現量逐漸下降,而在Wwox-/- MEFs中則無此現象。利用lentiviral shRNA抑制SCC-15細胞中WWOX表現後,再給予血清缺乏的壓力,結果顯示Bcl-XL及Mcl-1的表現量並無明顯降低之情形。另一方面,於Wwox-/- MEFs中回補WWOX/Wwox,在血清缺乏情況下,Bcl-XL及Mcl-1的表現量則會降低。總結而言,血清缺乏導致細胞內WWOX/Wwox表現量上升,進一步使抗細胞凋亡蛋白質Bcl-XL及Mcl-1表現下降,最後導致細胞死亡。

關鍵詞: 血清缺乏、細胞凋亡、氧化壓力
英文摘要 Abstract
Tumor suppressor WW domain-containing oxidoreductase is encoded by human fragile WWOX gene. Mutation of WWOX gene has been found in various types of human cancers and is associated with cancer progression. However, it remains largely unclear whether stress responses regulate WWOX/Wwox expression. Our results showed that serum deprivation and hydrogen peroxide treatment upregulated WWOX gene transcription and protein expression in SCC-15 cells and Wwox+/+ mouse embryonic fibroblasts (MEFs). Next, we demonstrated that serum deprivation induced higher levels of reactive oxygen species and cell death in Wwox+/+ MEFs compared with Wwox-/- MEFs. Anti-apoptotic Bcl-2 family proteins have been shown to regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that protein expression levels of Bcl-XL and Mcl-1 were downregulated in Wwox+/+ but not in Wwox-/- MEFs upon serum starvation. In SCC-15 cells expressing lentiviral shRNA targeting WWOX, serum starvation failed to downregulate Bcl-XL and Mcl-1 protein expression. Replenishment of ectopic WWOX induced downregulation of Bcl-XL protein in Wwox-/- MEFs after serum starvation. In conclusion, serum starvation increases WWOX/Wwox expression in cells, thus downregulating the expression of Bcl-XL and Mcl-1 proteins and further inducing cell death.

Keywords: serum starvation, Bcl-2 family, oxidative stress
論文目次 Contents
中文摘要 I
Abstract II
Acknowledgement III
Abbreviations IV
Contents V
Figure Index VIII
Introduction 1
WW domain-containing oxidoreductase 1
The tumor suppressor role of WWOX 2
The role of WWOX in apoptotic signaling upon stress 2
Other cellular role of WWOX 3
The prosurvival role of WWOX 3
The role of WWOX in differentiation 3
The role of WWOX in metabolism 3
B-cell CLL/lymphoma 2 (Bcl-2) family 4
The function of Bcl-2 family proteins in regulating apoptosis 5
The role of Bcl-2 family proteins in mitochondrial homeostasis 6
The nonapoptotic functions of Bcl-2 family proteins 6
Bcl-2 family proteins and diseases 7
Materials and Methods 8
A. Materials 8
A-1 Cell lines 8
A-2 Reagents and kits 8
A-3 Drugs 10
A-4 Antibodies 11
A-5 shRNA clones (bought from RNAi core) 11
A-6 Forward and reverse PCR primers 11
A-7 Consumables 12
A-8 Instruments 13
B. Methods 14
B-1 Cell culture 14
B-2 Cell viability assay 15
B-3 Plasmid DNA purification 16
B-4 Transient transfection by electroporation 18
B-5 Lentiviral shRNA knockdown 19
B-6 Protein extraction 19
B-7 Quantification and normalization of protein content 21
B-8 Sodium dodecyl sulfate-polyacrylaminde gel electrophoresis (SDS-PAGE) and Western blotting 21
B-9 RNA extraction 23
B-10 Reverse transcription polymerase chain reaction (RT-PCR) 25
B-11 Polymerase chain reaction (semi-PCR) 27
B-12 Real-time polymerase chain reaction (Real-time PCR) 29
B-13 Flow cytometry : cell cycle analysis by PI staining 30
B-14 Measurement of MMP 31
B-15 Measurement of ROS 32
Results 33
Stress stimulation increases the expression of WWOX protein in cancer cells 33
Stress stimulation increases WWOX mRNA levels in SCC-15 cells 33
Stress stimulation increases mRNA and protein levels of Wwox in mouse embryonic fibroblasts (MEFs) 33
Wwox+/+ MEFs are more sensitive to starvation-induced cell death than Wwox-/- MEFs 34
WWOX downregulates protein expression levels of Bcl-XL and Mcl-1 following serum starvation 35
Wwox-mediated Bcl-XL/Mcl-1 downregulation is not due to the reduction of Bcl-XL/Mcl-1 mRNA levels 36
WWOX increases Bcl-XL/Mcl-1 protein degradation through lysosome-dependent pathway 36
Serum starvation induces higher levels of ROS production and DNA damage in Wwox+/+ than in Wwox-/- MEFs 37
Discussion 38
The expression and activation of WWOX upon stress 38
The transcriptional regulation of WWOX 39
Role of WWOX in the regulation of Bcl-2 family proteins 40
Other possibility of WWOX on regulating the expression of Bcl-XL and Mcl-1 40
The protein stability of Bcl-XL and Mcl-1 41
The importance of the promoter region of WWOX upon serum starvation-induced WWOX gene activation 42
Role of WWOX in serum starvation-induced ROS generation 42
Conclusion 44
References 45
Figures 53
Appendix 69
Resume 70
參考文獻 References
1. Bednarek, A.K., et al., WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res, 2000. 60(8): p. 2140-5.
2. Ried, K., et al., Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum Mol Genet, 2000. 9(11): p. 1651-63.
3. Chang, N.S., et al., Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. J Biol Chem, 2001. 276(5): p. 3361-70.
4. Chen, S.T., et al., Light-induced retinal damage involves tyrosine 33 phosphorylation, mitochondrial and nuclear translocation of WW domain-containing oxidoreductase in vivo. Neuroscience, 2005. 130(2): p. 397-407.
5. Lewandowska, U., et al., WWOX, the tumour suppressor gene affected in multiple cancers. J Physiol Pharmacol, 2009. 60 Suppl 1: p. 47-56.
6. Sudol, M., et al., Characterization of a novel protein-binding module--the WW domain. FEBS Lett, 1995. 369(1): p. 67-71.
7. Zarrinpar, A. and W.A. Lim, Converging on proline: the mechanism of WW domain peptide recognition. Nature structural biology, 2000. 7(8): p. 611-613.
8. Ludes-Meyers, J.H., et al., WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins. Oncogene, 2004. 23(29): p. 5049-55.
9. Aqeilan, R.I., et al., Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci U S A, 2004. 101(13): p. 4401-6.
10. Lin, D., et al., p73 participates in WWOX-mediated apoptosis in leukemia cells. Int J Mol Med, 2013. 31(4): p. 849-54.
11. Aqeilan, R.I., et al., Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer Res, 2004. 64(22): p. 8256-61.
12. Aqeilan, R.I., et al., WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res, 2005. 65(15): p. 6764-72.
13. Aqeilan, R.I., et al., Association of Wwox with ErbB4 in breast cancer. Cancer Res, 2007. 67(19): p. 9330-6.
14. Jin, C., et al., PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. Biochem Biophys Res Commun, 2006. 341(3): p. 784-91.
15. Gaudio, E., et al., Physical association with WWOX suppresses c-Jun transcriptional activity. Cancer Res, 2006. 66(24): p. 11585-9.
16. Aqeilan, R.I., et al., The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism. J Biol Chem, 2008. 283(31): p. 21629-39.
17. Kurek, K.C., et al., Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Res, 2010. 70(13): p. 5577-86.
18. Ludes-Meyers, J.H., et al., WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenet Genome Res, 2003. 100(1-4): p. 101-10.
19. Chang, N.S., et al., WW domain-containing oxidoreductase: a candidate tumor suppressor. Trends Mol Med, 2007. 13(1): p. 12-22.
20. Su, W.-P., et al., WW Domain-containing oxidoreductase is a potential receptor for sex steroid hormones. Sex Hormones, 2012: p. 333-351.
21. Chang, N.S., J. Doherty, and A. Ensign, JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J Biol Chem, 2003. 278(11): p. 9195-202.
22. Chang, N.S., et al., WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53. J Biol Chem, 2005. 280(52): p. 43100-8.
23. Mahajan, N.P., et al., Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res, 2005. 65(22): p. 10514-23.
24. Smith, D.I., et al., Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett, 2006. 232(1): p. 48-57.
25. Kuroki, T., et al., The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin Cancer Res, 2004. 10(7): p. 2459-65.
26. Aqeilan, R.I., et al., Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A, 2007. 104(10): p. 3949-54.
27. Göthlin Eremo, A., et al., Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncol Rep, 2013. 29(4): p. 1467-1474.
28. Iliopoulos, D., et al., Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of Wwox expression. Clin Cancer Res, 2007. 13(1): p. 268-74.
29. Fabbri, M., et al., WWOX gene restoration prevents lung cancer growth in vitro and in vivo. Proc Natl Acad Sci U S A, 2005. 102(43): p. 15611-6.
30. Jamshidiha, M., et al., Primary WWOX phosphorylation and JNK activation during etoposide induces cytotoxicity in HEK293 cells. Daru, 2010. 18(2): p. 141-5.
31. Hong, Q., et al., Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells. PLoS One, 2009. 4(6): p. e5755.
32. Watanabe, A., et al., An opposing view on WWOX protein function as a tumor suppressor. Cancer Res, 2003. 63(24): p. 8629-33.
33. Sze, C.I., et al., Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro. A potential role in Alzheimer's disease. J Biol Chem, 2004. 279(29): p. 30498-506.
34. Chen, S.T., et al., Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system. Neuroscience, 2004. 124(4): p. 831-9.
35. Lai, F.J., et al., WOX1 is essential for UVB irradiation-induced apoptosis and down-regulated via translational blockade in UVB-induced cutaneous squamous cell carcinoma in vivo. Clin Cancer Res, 2005. 11(16): p. 5769-77.
36. O'Keefe, L.V., et al., Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species. Hum Mol Genet, 2011. 20(3): p. 497-509.
37. Oliva, C.R., et al., Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One, 2011. 6(9): p. e24665.
38. Dayan, S., et al., Common chromosomal fragile site FRA16D tumor suppressor WWOX gene expression and metabolic reprograming in cells. Genes Chromosomes Cancer, 2013.
39. Gross, A., J.M. McDonnell, and S.J. Korsmeyer, BCL-2 family members and the mitochondria in apoptosis. Genes Dev, 1999. 13(15): p. 1899-1911.
40. Adams, J.M. and S. Cory, The Bcl-2 protein family: arbiters of cell survival. Science, 1998. 281(5381): p. 1322-1326.
41. Tsujimoto, Y., et al., Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science, 1984. 226(4678): p. 1097-9.
42. Kelekar, A. and C.B. Thompson, Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol, 1998. 8(8): p. 324-330.
43. Cheng, E.H.-Y., et al., BCL-2, BCL-X< sub> L Sequester BH3 Domain-Only Molecules Preventing BAX-and BAK-Mediated Mitochondrial Apoptosis. Mol Cell, 2001. 8(3): p. 705-711.
44. Letai, A., et al., Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2002. 2(3): p. 183-92.
45. Kim, H., et al., Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol, 2006. 8(12): p. 1348-58.
46. Ouyang, L., et al., Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif, 2012. 45(6): p. 487-498.
47. Strasser, A., S. Cory, and J.M. Adams, Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J, 2011. 30(18): p. 3667-83.
48. Kischkel, F.C., et al., Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J, 1995. 14(22): p. 5579-88.
49. Gupta, S., Molecular signaling in death receptor and mitochondrial pathways of apoptosis (Review). International journal of oncology, 2003. 22(1): p. 15.
50. Kuwana, T. and D.D. Newmeyer, Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol, 2003. 15(6): p. 691-9.
51. Billen, L.P., et al., Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol, 2008. 6(6): p. e147.
52. Shimizu, S., M. Narita, and Y. Tsujimoto, Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature, 1999. 399(6735): p. 483-487.
53. Kroemer, G., L. Galluzzi, and C. Brenner, Mitochondrial membrane permeabilization in cell death. Physiol Rev, 2007. 87(1): p. 99-163.
54. Rodriguez, D., D. Rojas-Rivera, and C. Hetz, Integrating stress signals at the endoplasmic reticulum: The BCL-2 protein family rheostat. Biochim Biophys Acta, 2011. 1813(4): p. 564-74.
55. Eckenrode, E.F., et al., Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem, 2010. 285(18): p. 13678-84.
56. White, C., et al., The endoplasmic reticulum gateway to apoptosis by Bcl-X(L) modulation of the InsP3R. Nat Cell Biol, 2005. 7(10): p. 1021-8.
57. Huang, H., et al., An Interaction between Bcl-xL and the Voltage-dependent Anion Channel (VDAC) Promotes Mitochondrial Ca2+ Uptake. J Biol Chem, 2013. 288(27): p. 19870-81.
58. Wang, X., et al., Bcl-2 proteins regulate ER membrane permeability to luminal proteins during ER stress-induced apoptosis. Cell Death Differ, 2011. 18(1): p. 38-47.
59. Lindenboim, L., et al., Regulation of stress-induced nuclear protein redistribution: a new function of Bax and Bak uncoupled from Bcl-x(L). Cell Death Differ, 2010. 17(2): p. 346-59.
60. Gottlieb, E., M.G. Vander Heiden, and C.B. Thompson, Bcl-xL Prevents the Initial Decrease in Mitochondrial Membrane Potential and Subsequent Reactive Oxygen Species Production during Tumor Necrosis Factor Alpha-Induced Apoptosis. Mol Cell Biol, 2000. 20(15): p. 5680-5689.
61. Lee, S.B., et al., Bcl-XL prevents serum deprivation-induced oxidative stress mediated by Romo1. Oncol Rep, 2011. 25(5): p. 1337-42.
62. Yi, C.H., et al., Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell, 2011. 146(4): p. 607-20.
63. Marquez, R.T. and L. Xu, Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res, 2012. 2(2): p. 214-21.
64. Maiuri, M.C., et al., Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J, 2007. 26(10): p. 2527-39.
65. Pattingre, S., et al., Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 2005. 122(6): p. 927-39.
66. Yeretssian, G., et al., Non-apoptotic role of BID in inflammation and innate immunity. Nature, 2011. 474(7349): p. 96-9.
67. Karbowski, M., et al., Role of Bax and Bak in mitochondrial morphogenesis. Nature, 2006. 443(7112): p. 658-62.
68. Nakayama, K., et al., Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A, 1994. 91(9): p. 3700-4.
69. Packham, G., et al., Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Genes Dev, 1998. 12(16): p. 2475-2487.
70. Bouillet, P., et al., Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science, 1999. 286(5445): p. 1735-8.
71. Rathmell, J.C., et al., Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol, 2002. 3(10): p. 932-9.
72. Motoyama, N., et al., bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation. J Exp Med, 1999. 189(11): p. 1691-8.
73. Rhodes, M.M., et al., Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin. Blood, 2005. 106(5): p. 1857-63.
74. Abe-Dohmae, S., et al., Bcl-2 gene is highly expressed during neurogenesis in the central nervous system. Biochem Biophys Res Commun, 1993. 191(3): p. 915-21.
75. Sasaki, T., et al., Bcl2 enhances survival of newborn neurons in the normal and ischemic hippocampus. J Neurosci Res, 2006. 84(6): p. 1187-96.
76. Rheinwald, J.G. and M.A. Beckett, Tumorigenic Keratinocyte Lines Requiring Anchorage and Fibroblast Support Cultured from Human Squamous Cell Carcinomas. Cancer Res, 1981. 41(5): p. 1657-1663.
77. Braun, F., et al., Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition. PLoS One, 2011. 6(8): p. e23577.
78. Garrido, C., et al., HSP27 as a mediator of confluence-dependent resistance to cell death induced by anticancer drugs. Cancer Res, 1997. 57(13): p. 2661-7.
79. Pardee, A.B., A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A, 1974. 71(4): p. 1286-90.
80. Satoh, T., et al., Survival factor-insensitive generation of reactive oxygen species induced by serum deprivation in neuronal cells. Brain Res, 1996. 733(1): p. 9-14.
81. Liu, S.Y., et al., Albumin prevents reactive oxygen species-induced mitochondrial damage, autophagy, and apoptosis during serum starvation. Apoptosis, 2012. 17(11): p. 1156-69.
82. Vafa, O., et al., c-Myc Can Induce DNA Damage, Increase Reactive Oxygen Species, and Mitigate p53 Function: A Mechanism for Oncogene-Induced Genetic Instability. Mol Cell, 2002. 9(5): p. 1031-1044.
83. Del Mare, S., Z. Salah, and R.I. Aqeilan, WWOX: its genomics, partners, and functions. J Cell Biochem, 2009. 108(4): p. 737-45.
84. Chang, N.-S., et al., 17[beta]-Estradiol upregulates and activates WOX1//WWOXv1 and WOX2//WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo. Oncogene, 2004. 24(4): p. 714-723.
85. Hsu, L.-J., et al., Transforming growth factor β1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1. Journal of Biological Chemistry, 2009. 284(23): p. 16049-16059.
86. Ishii, H., et al., Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites. Molecular cancer research, 2005. 3(3): p. 130-138.
87. Thavathiru, E., et al., Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR. Mol Carcinog, 2005. 44(3): p. 174-82.
88. Casper, A.M., et al., ATR regulates fragile site stability. Cell, 2002. 111(6): p. 779-789.
89. Luczak, M.W. and P.P. Jagodziński, The role of DNA methylation in cancer development. Folia Histochemica et Cytobiologica, 2006. 44(3): p. 143-142.
90. Iliopoulos, D., et al., Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene, 2005. 24(9): p. 1625-1633.
91. Liu, C.J., et al., miR‐134 induces oncogenicity and metastasis in head and neck carcinoma through targeting WWOX gene. International Journal of Cancer, 2013.
92. Kimura, M., et al., Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells. Cancer Sci, 2011. 102(5): p. 983-90.
93. Chang, N.-S., et al., Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochemical Pharmacology, 2003. 66(8): p. 1347-1354.
94. Xue, S., K. Calvin, and H. Li, RNA recognition and cleavage by a splicing endonuclease. Science, 2006. 312(5775): p. 906-10.
95. Holcik, M., et al., A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection. Nat Cell Biol, 1999. 1(3): p. 190-2.
96. Coldwell, M.J., et al., Initiation of Apaf-1 translation by internal ribosome entry. Oncogene, 2000. 19(7): p. 899-905.
97. Holcik, M., et al., Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene, 2000. 19(36): p. 4174-4177.
98. Stoneley, M. and A.E. Willis, Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. Oncogene, 2004. 23(18): p. 3200-7.
99. Zhong, Q., et al., Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell, 2005. 121(7): p. 1085-1095.
100. Lu, C., et al., Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway. FEBS Lett, 2008. 582(18): p. 2703-2708.
101. Risbud, M.V., et al., Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine (Phila Pa 1976), 2005. 30(8): p. 882-889.
102. Wang, Y. and M.F. Lou, The regulation of NADPH oxidase and its association with cell proliferation in human lens epithelial cells. Invest Ophthalmol Vis Sci, 2009. 50(5): p. 2291-300.
103. Chen, Y., et al., Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci, 2007. 120(23): p. 4155-4166.

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