進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-3108202011505200
論文名稱(中文) 探討WWOX對皮膚發育與恆定之調控
論文名稱(英文) WWOX regulates skin development and homeostasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 108
學期 2
出版年 109
研究生(中文) 周映岑
研究生(英文) Ying-Tsen Chou
學號 S58001276
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-徐麗君
召集委員-張南山
口試委員-王育民
口試委員-蔣輯武
口試委員-詹明修
口試委員-賴豐傑
中文關鍵字 含雙色胺酸功能區氧化還原酶  角質細胞增生  角質細胞分化  幹細胞  脂肪細胞 
英文關鍵字 WWOX  keratinocyte proliferation  keratinocyte differentiation  stem cells  adipocytes 
學科別分類
中文摘要 含雙色胺酸功能區氧化還原酶WWOX是著名的腫瘤抑制子,具有促細胞凋亡(pro-apoptosis)的功能。近期研究指出:WWOX基因有缺陷之人類或Wwox基因剔除鼠展現嚴重的神經病徵、發育遲緩以及發育早期之個體死亡現象,顯示WWOX於維持正常組織的生理功能及恆定(homeostasis)上扮演重要角色。皮膚覆蓋於個體表面,可防止體內水份散失,並維持體溫穩定,對於個體的生理功能及個體存活十分重要。過去已發現:正常人類皮膚中,基底層細胞(basal cells)表現WWOX蛋白,且在分化的表層細胞中(suprabasal cells),WWOX蛋白的表現量有增強的現象。在WWOX基因缺陷下,皮膚的發育及恆定維持是否受到改變、並影響個體存活仍不清楚。本論文著重探討WWOX對皮膚的發育及生理功能之影響。我們發現:Wwox基因剔除鼠之皮膚細胞增生及分化均顯著地下降,但細胞凋亡卻增加。於人類皮膚角質細胞 (human keratinocytes)-HaCaT細胞中抑制WWOX蛋白表現,亦使得細胞增生及分化均減少。此外,相較於野生型小鼠,Wwox基因剔除鼠在早期發育階段 (出生後7天),其毛囊幹細胞(hair follicle stem cells)仍持續高度增生而未進入靜止狀態(quiescence),而21天大的Wwox基因剔除鼠之幹細胞數量亦有顯著減少之情形。在分子機制上,Wwox基因剔除鼠之皮膚Wnt/beta-catenin與ERK兩種訊息傳遞路徑亦顯著減少。這些現象使得Wwox基因剔除鼠之皮膚含水量減少、皮膚厚度減少以及毛髮的發育遲緩。有趣的是,我們也發現了Wwox基因剔除鼠在出生3天時,其脂肪生成重要的轉錄因子(transcription factor)PPAR-gamma顯著降低,而脂肪發育也明顯遲緩。直至出生21天,Wwox基因剔除鼠缺乏皮下脂肪層且體溫顯著降低。總結以上結果,WWOX於幫助皮膚及及脂肪的發育與恆定維持扮演著重要的調控角色。
英文摘要 WW domain-containing oxidoreductase (WWOX) is initially known as a proapoptotic tumor suppressor. Substantial studies have shown that WWOX-deficient human patients and Wwox-knockout mice display severe neuronal diseases, growth retardation and early death during postnatal developmental stages, implying the importance of WWOX in physiological functions, tissue development and homeostasis. Maintenance of skin integrity is crucial to animal survival by preventing body from infection, water loss and hypothermia. In normal human epidermis, WWOX is abundant in proliferating epidermal basal cells and its expression is increased in intensity toward the superficial differentiated cells. However, whether skin development and homeostasis are affected under Wwox deficiency that correlates with early death is still unknown. In this study, we determined that Wwox-/- epidermis displayed decreased keratinocyte proliferation and differentiation but increased apoptosis. Downregulated proliferation and differentiation were also found in WWOX-knockdown HaCaT cells. We also found that the Wwox-/- hair follicle stem cells were not quiescence but had higher proliferative activities at postnatal day (P)7 and the stem cells were depleted at P21. These events caused reduced epidermal hydration state, epidermal thickness and delayed hair development in Wwox-/- mice. Mechanistically, we found that both prosurvival Wnt/beta-catenin and ERK signal pathways were downregulated. In addition, Wwox-/- mice exhibited delayed adipocyte development at P3, associating with downregulated PPAR-gamma expression, the key adipogenic transcription factor. These lead to severe loss of subcutaneous adipose tissue and significant hypothermia at P21. Our studies reveal that WWOX plays important roles in regulating epidermal and adipocyte development and homeostasis, which may also in part, account for the aberrant WWOX/Wwox organism phenotype.
論文目次 中文摘要 I
Abstract II
誌謝 IV
Contents VI
Figure contents IX
Appendix contents XI
Chapter 1. Introduction 1
1.1. WW-domain containing oxidoreductase (WWOX): 1
1.1.1. Genetic background 1
1.1.2. WWOX protein structure 1
1.1.3. Tumor suppressor WWOX 4
1.1.4. WWOX in physiological functions and tissue homeostasis 5
1.1.5. Involvement of WWOX in multiple signaling pathways 6
1.1.5.1. WWOX: a proapoptotic protein 6
1.1.5.2. The involvement of WWOX in cell growth 9
1.2. The skin 10
1.2.1. Epidermal structure and homeostasis 10
1.2.2. Signaling in epidermal differentiation 12
1.2.3. Signaling in epidermal proliferation 15
1.2.4. Hair follicle morphogenesis and maturation 16
1.2.5. Hair follicle stem cells 17
1.2.6. The dermis 18
1.2.7. The hypodermis 19
1.3. Rationales and objectives 20
Chapter 2. Materials and Methods 22
2.1. Animals 22
2.2. Cell culture 22
2.3. Generation of lentiviral knockdown cell lines 23
2.4. Hematoxylin & Eosin (H&E) staining 23
2.5. Collagen staining 24
2.6. Fat staining 24
2.7. Transmission electron microscopy 24
2.8. Body temperature, hydration state, and transepidermal water loss (TEWL) measurement 25
2.9. Immunohistochemical and immunofluorescence staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay 25
2.10. Western blotting 27
2.11. Flow cytometry analysis 28
2.12. Antibodies 28
2.13. Statistical analysis and quantification analysis 29
Chapter 3. Results 30
3.1. Wwox depletion results in reduced epidermal integrity 30
3.2. WWOX is required for keratinocyte differentiation and stratification 31
3.3. WWOX regulates keratinocyte cell proliferation and survival 32
3.4. Wwox depletion leads to increased apoptosis in epidermal keratinocytes 33
3.5. Wwox depletion delays postnatal HF development 34
3.6. Wwox depletion compromises stem cell maintenance in mouse skin 35
3.7. WWOX deficient reduces beta-catenin expression 36
3.8. Wwox depletion leads to reduced dermal collagen contents 37
3.9. Wwox depletion leads to loss of subcutaneous fat and hypothermia 38
3.10. Summary 39
Chapter 4. Discussion and conclusion 40
Chapter 5. References 48
Chapter 6. Figures 62
Appendix 106
Curriculum Vitae 112

參考文獻 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. 60, 2140-2145 (2000).
2. Bednarek, A.K., et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 61, 8068-8073 (2001).
3. 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. 9, 1651-1663 (2000).
4. Chang, N.S., Hsu, L.J., Lin, Y.S., Lai, F.J. & Sheu, H.M. WW domain-containing oxidoreductase: a candidate tumor suppressor. Trends Mol. Med. 13, 12-22 (2007).
5. Richards, R.I., Choo, A., Lee, C.S., Dayan, S. & O'Keefe, L. WWOX, the chromosomal fragile site FRA16D spanning gene: its role in metabolism and contribution to cancer. Exp. Biol. Med. (Maywood) 240, 338-344 (2015).
6. Sudol, M. Structure and function of the WW domain. Prog. Biophys. Mol. Biol. 65, 113-132 (1996).
7. Ilsley, J.L., Sudol, M. & Winder, S.J. The WW domain: linking cell signalling to the membrane cytoskeleton. Cell. Signal. 14, 183-189 (2002).
8. Kasanov, J., Pirozzi, G., Uveges, A.J. & Kay, B.K. Characterizing Class I WW domains defines key specificity determinants and generates mutant domains with novel specificities. Chem. Biol. 8, 231-241 (2001).
9. Sudol, M. & Harvey, K.F. Modularity in the Hippo signaling pathway. Trends Biochem. Sci. 35, 627-633 (2010).
10. Aqeilan, R.I., et al. Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc. Natl. Acad. Sci. U. S. A. 101, 4401-4406 (2004).
11. Aqeilan, R.I., et al. Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer Res. 64, 8256-8261 (2004).
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. 65, 6764-6772 (2005).
13. Aqeilan, R.I., et al. Association of Wwox with ErbB4 in breast cancer. Cancer Res. 67, 9330-9336 (2007).
14. Gaudio, E., et al. Physical association with WWOX suppresses c-Jun transcriptional activity. Cancer Res. 66, 11585-11589 (2006).
15. Aqeilan, R.I., et al. The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism. J. Biol. Chem. 283, 21629-21639 (2008).
16. Abu-Odeh, M., et al. Characterizing WW domain interactions of tumor suppressor WWOX reveals its association with multiprotein networks. J. Biol. Chem. 289, 8865-8880 (2014).
17. Schrock, M.S., et al. Wwox-Brca1 interaction: role in DNA repair pathway choice. Oncogene 36, 2215-2227 (2017).
18. Bouteille, N., et al. Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein. Oncogene 28, 2569-2580 (2009).
19. Ferguson, B.W., et al. The cancer gene WWOX behaves as an inhibitor of SMAD3 transcriptional activity via direct binding. BMC Cancer 13, 593 (2013).
20. McDonald, C.B., et al. Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors. J. Mol. Biol. 422, 58-74 (2012).
21. Schuchardt, B.J., et al. Molecular origin of the binding of WWOX tumor suppressor to ErbB4 receptor tyrosine kinase. Biochemistry 52, 9223-9236 (2013).
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. 280, 43100-43108 (2005).
23. Chang, N.S., Doherty, J. & Ensign, A. JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J. Biol. Chem. 278, 9195-9202 (2003).
24. Chang, N.S., et al. Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. J. Biol. Chem. 276, 3361-3370 (2001).
25. Chang, R., et al. Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nat. Commun. 9, 3486 (2018).
26. Huang, S.S., et al. Role of WW domain-containing oxidoreductase WWOX in driving T cell acute lymphoblastic leukemia maturation. J. Biol. Chem. 291, 17319-17331 (2016).
27. Salah, Z., et al. Tumor suppressor WWOX binds to ΔNp63α and sensitizes cancer cells to chemotherapy. Cell Death Dis. 4, e480 (2013).
28. Farooq, A. Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor. Exp. Biol. Med. (Maywood) 240, 361-374 (2015).
29. Del Mare, S., Salah, Z. & Aqeilan, R.I. WWOX: its genomics, partners, and functions. J. Cell. Biochem. 108, 737-745 (2009).
30. 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. 279, 30498-30506 (2004).
31. Wang, H.Y., et al. WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β. Cell Death Differ. 19, 1049-1059 (2012).
32. Kumar, R., et al. HumCFS: a database of fragile sites in human chromosomes. BMC Genomics 19, 985 (2019).
33. 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. 11, 5769-5777 (2005).
34. Pimenta, F.J., et al. Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. Int. J. Cancer 118, 1154-1158 (2006).
35. Kuroki, T., et al. Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res. 62, 2258-2260 (2002).
36. Guo, W., et al. Decreased expression of WWOX in the development of esophageal squamous cell carcinoma. Mol. Carcinog. 52, 265-274 (2013).
37. Liu, C.J., et al. miR-134 induces oncogenicity and metastasis in head and neck carcinoma through targeting WWOX gene. Int. J. Cancer 134, 811-821 (2014).
38. Ekizoglu, S., Bulut, P., Karaman, E., Kilic, E. & Buyru, N. Epigenetic and genetic alterations affect the WWOX gene in head and neck squamous cell carcinoma. PLoS One 10, e0115353 (2015).
39. Singchat, W., et al. Genomic alteration in head and neck squamous cell carcinoma (HNSCC) cell lines inferred from karyotyping, molecular cytogenetics, and array comparative genomic hybridization. PLoS One 11, e0160901 (2016).
40. Giarnieri, E., et al. Oncosuppressor proteins of fragile sites are reduced in cervical cancer. Cancer Lett. 289, 40-45 (2010).
41. Nunez, M.I., et al. Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status. Breast Cancer Res. Treat. 89, 99-105 (2005).
42. Pospiech, K., Pluciennik, E. & Bednarek, A.K. WWOX tumor suppressor gene in breast cancer, a historical perspective and future directions. Front. Oncol. 8, 345 (2018).
43. Bloomston, M., et al. Coordinate loss of fragile gene expression in pancreatobiliary cancers: correlations among markers and clinical features. Ann. Surg. Oncol. 16, 2331-2338 (2009).
44. Becker, S., et al. Functional and clinical characterization of the putative tumor suppressor WWOX in non-small cell lung cancer. J. Thorac. Oncol. 6, 1976-1983 (2011).
45. Liu, S.Y., Chiang, M.F. & Chen, Y.J. Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma. Exp. Biol. Med. (Maywood) 240, 315-323 (2015).
46. Yu, K., et al. Association study of a functional copy number variation in the WWOX gene with risk of gliomas among Chinese people. Int. J. Cancer 135, 1687-1691 (2014).
47. Winardi, W., et al. Reduced WWOX protein expression in human astrocytoma. Neuropathology 33, 621-627 (2013).
48. Kosla, K., et al. Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme. J. Neurooncol. 101, 207-213 (2011).
49. Schrock, M.S. & Huebner, K. WWOX: a fragile tumor suppressor. Exp. Biol. Med. (Maywood) 240, 296-304 (2015).
50. Lo, J.Y., Chou, Y.T., Lai, F.J. & Hsu, L.J. Regulation of cell signaling and apoptosis by tumor suppressor WWOX. Exp. Biol. Med. (Maywood) 240, 383-391 (2015).
51. Baykara, O., et al. WWOX gene may contribute to progression of non-small-cell lung cancer (NSCLC). Tumour Biol. 31, 315-320 (2010).
52. Kuroki, T., et al. The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin. Cancer Res. 10, 2459-2465 (2004).
53. Qu, J., Lu, W., Li, B., Lu, C. & Wan, X. WWOX induces apoptosis and inhibits proliferation in cervical cancer and cell lines. Int. J. Mol. Med. 31, 1139-1147 (2013).
54. Lin, J.T., et al. WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase. Cell Cycle 14, 408-416 (2015).
55. Iliopoulos, D., et al. Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of Wwox expression. Clin. Cancer Res. 13, 268-274 (2007).
56. Fabbri, M., et al. WWOX gene restoration prevents lung cancer growth in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 102, 15611-15616 (2005).
57. Nakayama, S., et al. Role of the WWOX gene, encompassing fragile region FRA16D, in suppression of pancreatic carcinoma cells. Cancer Sci. 99, 1370-1376 (2008).
58. Janczar, S., et al. WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response. Cell Death Dis. 8, e2955 (2017).
59. Aqeilan, R.I., et al. Targeted deletion of Wwox reveals a tumor suppressor function. Proc. Natl. Acad. Sci. U. S. A. 104, 3949-3954 (2007).
60. Chou, P.Y., et al. Strategies by which WWOX-deficient metastatic cancer cells utilize to survive via dodging, compromising, and causing damage to WWOX-positive normal microenvironment. Cell Death Discov. 5, 97 (2019).
61. Abdeen, S.K., Ben-David, U., Shweiki, A., Maly, B. & Aqeilan, R.I. Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer. Cell Death Dis. 9, 832 (2018).
62. Majbil, D.A. & Merza, M.S. Immunohistochemical evaluation of FHIT and WWOX expression in normal oral mucosa, oral epithelial dysplasia and oral squamous cell carcinoma. J. Baghdad Coll. Dent. 26, 6 (2014).
63. Watanabe, A., et al. An opposing view on WWOX protein function as a tumor suppressor. Cancer Res. 63, 8629-8633 (2003).
64. Chang, N.S., et al. 17beta-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 24, 714-723 (2005).
65. Nowakowska, M., Pospiech, K., Lewandowska, U., Piastowska-Ciesielska, A.W. & Bednarek, A.K. Diverse effect of WWOX overexpression in HT29 and SW480 colon cancer cell lines. Tumour Biol. 35, 9291-9301 (2014).
66. Ferguson, B.W., et al. Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches. PLoS One 7, e36618 (2012).
67. Ludes-Meyers, J.H., et al. Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One 4, e7775 (2009).
68. Tochigi, Y., et al. Loss of Wwox causes defective development of cerebral cortex with hypomyelination in a rat model of lethal dwarfism with epilepsy. Int. J. Mol. Sci. 20, 3596 (2019).
69. Nunez, M.I., Ludes-Meyers, J. & Aldaz, C.M. WWOX protein expression in normal human tissues. J. Mol. Histol. 37, 115-125 (2006).
70. Abdeen, S.K., et al. Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype. J. Cell. Physiol. 228, 1377-1382 (2013).
71. Valduga, M., et al. WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period. J. Hum. Genet. 60, 267-271 (2015).
72. Tabarki, B., et al. Severe CNS involvement in WWOX mutations: description of five new cases. Am. J. Med. Genet. A 167A, 3209-3213 (2015).
73. Mignot, C., et al. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J. Med. Genet. 52, 61-70 (2015).
74. Abdel-Salam, G., et al. The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration. Orphanet J. Rare Dis. 9, 12 (2014).
75. Elsaadany, L., El-Said, M., Ali, R., Kamel, H. & Ben-Omran, T. W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report. BMC Med. Genet. 17, 53 (2016).
76. Ben-Salem, S., Al-Shamsi, A.M., John, A., Ali, B.R. & Al-Gazali, L. A novel whole exon deletion in WWOX gene causes early epilepsy, intellectual disability and optic atrophy. J. Mol. Neurosci. 56, 17-23 (2015).
77. Mallaret, M., et al. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 137, 411-419 (2014).
78. Chang, N.S., et al. Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochem. Pharmacol. 66, 1347-1354 (2003).
79. Hong, Q., et al. Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells. PLoS One 4, e5755 (2009).
80. Li, M.Y., et al. Dramatic co-activation of WWOX/WOX1 with CREB and NF-kappaB in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats. PLoS One 4, e7820 (2009).
81. Lo, C.P., et al. MPP+-induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1. Eur. J. Neurosci. 27, 1634-1646 (2008).
82. Chen, S.T., Chuang, J.I., Cheng, C.L., Hsu, L.J. & Chang, N.S. Light-induced retinal damage involves tyrosine 33 phosphorylation, mitochondrial and nuclear translocation of WW domain-containing oxidoreductase in vivo. Neuroscience 130, 397-407 (2005).
83. Qin, H.R., et al. A role for the WWOX gene in prostate cancer. Cancer Res. 66, 6477-6481 (2006).
84. Li, G., et al. Ectopic WWOX expression inhibits growth of 5637 bladder cancer cell in vitro and in vivo. Cell Biochem. Biophys. 73, 417-425 (2015).
85. Chen, J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 6, a026104 (2016).
86. Kastenhuber, E.R. & Lowe, S.W. Putting p53 in context. Cell 170, 1062-1078 (2017).
87. Wei, D., et al. WW domain containing oxidoreductase induces apoptosis in gallbladder-derived malignant cell by upregulating expression of P73 and PUMA. Tumour Biol. 35, 1539-1550 (2014).
88. Hsu, L.J., et al. Transforming growth factor beta1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1. J. Biol. Chem. 284, 16049-16059 (2009).
89. Massague, J. TGFbeta in Cancer. Cell 134, 215-230 (2008).
90. Hsu, L.J., et al. Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. Oncotarget 8, 19137-19155 (2017).
91. Chang, N.S., et al. Cloning and characterization of a novel transforming growth factor-beta1-induced TIAF1 protein that inhibits tumor necrosis factor cytotoxicity. Biochem. Biophys. Res. Commun. 253, 743-749 (1998).
92. Chou, P.Y., et al. A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism. Cell Commun. Signal. 17, 76 (2019).
93. Chang, J.Y., et al. TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death. Cell Death Dis. 3, e302 (2012).
94. Yang, W., et al. Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma. Oncol. Lett. 13, 3198-3204 (2017).
95. Lin, H.P., et al. Identification of an in vivo MEK/WOX1 complex as a master switch for apoptosis in T cell leukemia. Genes Cancer 2, 550-562 (2011).
96. Huang, S.S. & Chang, N.S. Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events. Exp. Biol. Med. (Maywood) 243, 137-147 (2018).
97. Qin, H.R., et al. Wwox suppresses prostate cancer cell growth through modulation of ErbB2-mediated androgen receptor signaling. Mol. Cancer Res. 5, 957-965 (2007).
98. Xiong, A., et al. Wwox suppresses breast cancer cell growth through modulation of the hedgehog-GLI1 signaling pathway. Biochem. Biophys. Res. Commun. 443, 1200-1205 (2014).
99. Veltri, A., Lang, C. & Lien, W.H. Concise review: Wnt signaling pathways in skin development and epidermal stem cells. Stem Cells 36, 22-35 (2018).
100. Brembeck, F.H., et al. Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions. Genes Dev. 18, 2225-2230 (2004).
101. El-Hage, P., et al. The tumor-suppressor WWOX and HDAC3 inhibit the transcriptional activity of the β-catenin coactivator BCL9-2 in breast cancer cells. Mol. Cancer Res. 13, 902-912 (2015).
102. Presland, R.B. & Dale, B.A. Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit. Rev. Oral Biol. Med. 11, 383-408 (2000).
103. Belokhvostova, D., et al. Homeostasis, regeneration and tumour formation in the mammalian epidermis. Int. J. Dev. Biol. 62, 571-582 (2018).
104. Yi, R. & Fuchs, E. MicroRNA-mediated control in the skin. Cell Death Differ. 17, 229-235 (2010).
105. Fuchs, E. Scratching the surface of skin development. Nature 445, 834-842 (2007).
106. Mader, S.S. in Understanding Human Anatomy & Physiology (McGraw-Hill Education; 9 edition New York, 2016).
107. Holbrook, K.A. Biologic structure and function: perspectives on morphologic approaches to the study of the granular layer keratinocyte. J. Invest. Dermatol. 92, 84S-104S (1989).
108. Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat. Rev. Mol. Cell Biol. 10, 207-217 (2009).
109. Eckhart, L., Lippens, S., Tschachler, E. & Declercq, W. Cell death by cornification. Biochim. Biophys. Acta 1833, 3471-3480 (2013).
110. Freeman, S.C. & Sonthalia, S. Histology, Keratohyalin Granules. in StatPearls (Treasure Island (FL), 2020).
111. Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 6, 328-340 (2005).
112. Simpson, C.L., Patel, D.M. & Green, K.J. Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 565-580 (2011).
113. Sumigray, K.D. & Lechler, T. Cell adhesion in epidermal development and barrier formation. Curr. Top. Dev. Biol. 112, 383-414 (2015).
114. Tinkle, C.L., Lechler, T., Pasolli, H.A. & Fuchs, E. Conditional targeting of E-cadherin in skin: insights into hyperproliferative and degenerative responses. Proc. Natl. Acad. Sci. U. S. A. 101, 552-557 (2004).
115. Tunggal, J.A., et al. E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions. EMBO J. 24, 1146-1156 (2005).
116. Wang, X., et al. E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo. PLoS Genet. 14, e1007609 (2018).
117. Alam, M. & Ratner, D. Cutaneous squamous-cell carcinoma. N. Engl. J. Med. 344, 975-983 (2001).
118. Erb, P., et al. Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol. Lett. 100, 68-72 (2005).
119. Sotiropoulou, P.A. & Blanpain, C. Development and homeostasis of the skin epidermis. Cold Spring Harb. Perspect. Biol. 4, a008383 (2012).
120. Soares, E. & Zhou, H. Master regulatory role of p63 in epidermal development and disease. Cell. Mol. Life Sci. 75, 1179-1190 (2018).
121. Mills, A.A., et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708-713 (1999).
122. Koster, M.I., Kim, S., Mills, A.A., DeMayo, F.J. & Roop, D.R. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 18, 126-131 (2004).
123. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275-280 (2005).
124. Senoo, M., Pinto, F., Crum, C.P. & McKeon, F. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129, 523-536 (2007).
125. Melino, G., Memmi, E.M., Pelicci, P.G. & Bernassola, F. Maintaining epithelial stemness with p63. Sci. Signal. 8, re9 (2015).
126. Hsu, Y.C., Li, L. & Fuchs, E. Emerging interactions between skin stem cells and their niches. Nat. Med. 20, 847-856 (2014).
127. Kopan, R. Notch signaling. Cold Spring Harb. Perspect. Biol. 4(2012).
128. Pan, Y., et al. gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev. Cell 7, 731-743 (2004).
129. Powell, B.C., Passmore, E.A., Nesci, A. & Dunn, S.M. The Notch signalling pathway in hair growth. Mech. Dev. 78, 189-192 (1998).
130. Blanpain, C., Lowry, W.E., Pasolli, H.A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022-3035 (2006).
131. Williams, S.E., Beronja, S., Pasolli, H.A. & Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470, 353-358 (2011).
132. Wang, X., Pasolli, H.A., Williams, T. & Fuchs, E. AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis. J. Cell Biol. 183, 37-48 (2008).
133. Menon, G.K., Grayson, S. & Elias, P.M. Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ion-capture cytochemistry. J. Invest. Dermatol. 84, 508-512 (1985).
134. Celli, A., et al. The epidermal Ca(2+) gradient: measurement using the phasor representation of fluorescent lifetime imaging. Biophys. J. 98, 911-921 (2010).
135. Bikle, D.D., Xie, Z. & Tu, C.L. Calcium regulation of keratinocyte differentiation. Expert Rev. Endocrinol. Metab. 7, 461-472 (2012).
136. Hennings, H., et al. Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 19, 245-254 (1980).
137. Pillai, S., Bikle, D.D., Hincenbergs, M. & Elias, P.M. Biochemical and morphological characterization of growth and differentiation of normal human neonatal keratinocytes in a serum-free medium. J. Cell. Physiol. 134, 229-237 (1988).
138. Elias, P.M., et al. Modulations in epidermal calcium regulate the expression of differentiation-specific markers. J. Invest. Dermatol. 119, 1128-1136 (2002).
139. Elsholz, F., Harteneck, C., Muller, W. & Friedland, K. Calcium--a central regulator of keratinocyte differentiation in health and disease. Eur. J. Dermatol. 24, 650-661 (2014).
140. Hennings, H. & Holbrook, K.A. Calcium regulation of cell-cell contact and differentiation of epidermal cells in culture. An ultrastructural study. Exp. Cell Res. 143, 127-142 (1983).
141. Zamansky, G.B., Nguyen, U. & Chou, I.N. An immunofluorescence study of the calcium-induced coordinated reorganization of microfilaments, keratin intermediate filaments, and microtubules in cultured human epidermal keratinocytes. J. Invest. Dermatol. 97, 985-994 (1991).
142. Pokutta, S., Herrenknecht, K., Kemler, R. & Engel, J. Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding. Eur. J. Biochem. 223, 1019-1026 (1994).
143. Scholl, F.A., et al. Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev. Cell 12, 615-629 (2007).
144. Dumesic, P.A., Scholl, F.A., Barragan, D.I. & Khavari, P.A. Erk1/2 MAP kinases are required for epidermal G2/M progression. J. Cell Biol. 185, 409-422 (2009).
145. Scholl, F.A., Dumesic, P.A. & Khavari, P.A. Mek1 alters epidermal growth and differentiation. Cancer Res. 64, 6035-6040 (2004).
146. Tarutani, M., Cai, T., Dajee, M. & Khavari, P.A. Inducible activation of Ras and Raf in adult epidermis. Cancer Res. 63, 319-323 (2003).
147. Khavari, T.A. & Rinn, J. Ras/Erk MAPK signaling in epidermal homeostasis and neoplasia. Cell Cycle 6, 2928-2931 (2007).
148. Lien, W.H. & Fuchs, E. Wnt some lose some: transcriptional governance of stem cells by Wnt/beta-catenin signaling. Genes Dev. 28, 1517-1532 (2014).
149. Choi, Y.S., et al. Distinct functions for Wnt/beta-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13, 720-733 (2013).
150. Nguyen, H., et al. Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nat. Genet. 41, 1068-1075 (2009).
151. Nguyen, H., Rendl, M. & Fuchs, E. Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127, 171-183 (2006).
152. Lim, X., et al. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342, 1226-1230 (2013).
153. Malanchi, I., et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452, 650-653 (2008).
154. Fuchs, E. & Nowak, J.A. Building epithelial tissues from skin stem cells. Cold Spring Harb. Symp. Quant. Biol. 73, 333-350 (2008).
155. Forni, M.F., Trombetta-Lima, M. & Sogayar, M.C. Stem cells in embryonic skin development. Biol. Res. 45, 215-222 (2012).
156. Liu, S., Zhang, H. & Duan, E. Epidermal development in mammals: key regulators, signals from beneath, and stem cells. Int. J. Mol. Sci. 14, 10869-10895 (2013).
157. Millar, S.E. Molecular mechanisms regulating hair follicle development. J. Invest. Dermatol. 118, 216-225 (2002).
158. Alonso, L. & Fuchs, E. The hair cycle. J. Cell Sci. 119, 391-393 (2006).
159. Alberts, B., et al. Epidermis and its renewal by stem cells. in Mol. Biol. Cell 1259-1267 (Garland Science, New York, 2002).
160. Nowak, J.A., Polak, L., Pasolli, H.A. & Fuchs, E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3, 33-43 (2008).
161. Wang, D., et al. MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway. Nat. Cell Biol. 15, 1153-1163 (2013).
162. Hsu, Y.C., Li, L. & Fuchs, E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935-949 (2014).
163. Blanpain, C., Lowry, W.E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635-648 (2004).
164. Ali, N.J.A., et al. Essential role of polarity protein Par3 for epidermal homeostasis through regulation of barrier function, keratinocyte differentiation, and stem cell maintenance. J. Invest. Dermatol. 136, 2406-2416 (2016).
165. Niessen, M.T., et al. aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation. J. Cell Biol. 202, 887-900 (2013).
166. Rognoni, E. & Watt, F.M. Skin cell heterogeneity in development, wound healing, and cancer. Trends Cell Biol. 28, 709-722 (2018).
167. Alexander, C.M., et al. Dermal white adipose tissue: a new component of the thermogenic response. J. Lipid Res. 56, 2061-2069 (2015).
168. Gavin, H.E. & Satchell, K.J.F. Surface hypothermia predicts murine mortality in the intragastric Vibrio vulnificus infection model. BMC Microbiol. 17, 136 (2017).
169. Ray, M.A., Johnston, N.A., Verhulst, S., Trammell, R.A. & Toth, L.A. Identification of markers for imminent death in mice used in longevity and aging research. J. Am. Assoc. Lab. Anim. Sci. 49, 282-288 (2010).
170. Lu, W., et al. Mixture of fibroblasts and adipose tissue-derived stem cells can improve epidermal morphogenesis of tissue-engineered skin. Cells Tissues Organs 195, 197-206 (2012).
171. Festa, E., et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761-771 (2011).
172. Donati, G., et al. Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors. Proc. Natl. Acad. Sci. U. S. A. 111, E1501-1509 (2014).
173. Guerrero-Juarez, C.F. & Plikus, M.V. Emerging nonmetabolic functions of skin fat. Nat. Rev. Endocrinol. 14, 163-173 (2018).
174. Kolarsick, P.A.J., Kolarsick, M.A. & Goodwin, C. Anatomy and physiology of the skin (chapter 1). in Site-Specific Cancer Series: Skin Cancer (eds. Muelhbauer, P. & McGowan, C.) 1-11 (Oncology Nursing Society, 2009).
175. Chang, J.Y., et al. Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain. Oncotarget 6, 3578-3589 (2015).
176. Cheng, Y.Y., et al. Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3beta-mediated epileptic seizure activity in mice. Acta Neuropathol. Commun. 8, 6 (2020).
177. Jensen, K.B., Driskell, R.R. & Watt, F.M. Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis. Nat. Protoc. 5, 898-911 (2010).
178. Chou, T.C., et al. Topical exposure to carbon disulfide induces epidermal permeability alterations in physiological and pathological changes. Toxicol. Lett. 158, 225-236 (2005).
179. Varghese, F., Bukhari, A.B., Malhotra, R. & De, A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One 9, e96801 (2014).
180. Rawlings, A.V. & Harding, C.R. Moisturization and skin barrier function. Dermatol. Ther. 17 Suppl 1, 43-48 (2004).
181. Deyrieux, A.F. & Wilson, V.G. In vitro culture conditions to study keratinocyte differentiation using the HaCaT cell line. Cytotechnology 54, 77-83 (2007).
182. Chang, S.E., Foster, S., Betts, D. & Marnock, W.E. DOK, a cell line established from human dysplastic oral mucosa, shows a partially transformed non-malignant phenotype. Int. J. Cancer 52, 896-902 (1992).
183. Poumay, Y. & Pittelkow, M.R. Cell density and culture factors regulate keratinocyte commitment to differentiation and expression of suprabasal K1/K10 keratins. J. Invest. Dermatol. 104, 271-276 (1995).
184. Liu, C.C., et al. WWOX phosphorylation, signaling, and role in neurodegeneration. Front. Neurosci. 12, 563 (2018).
185. Muller-Rover, S., et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol. 117, 3-15 (2001).
186. Kretzschmar, K. & Watt, F.M. Markers of epidermal stem cell subpopulations in adult mammalian skin. Cold Spring Harb. Perspect. Med. 4(2014).
187. Suzuki, Y., et al. Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett. 521, 67-71 (2002).
188. Senoo, M. Epidermal stem cells in homeostasis and wound repair of the skin. Adv. Wound Care (New Rochelle) 2, 273-282 (2013).
189. Lim, X. & Nusse, R. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb. Perspect. Biol. 5(2013).
190. McCubrey, J.A., et al. Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia 28, 15-33 (2014).
191. Voronkov, A. & Krauss, S. Wnt/beta-catenin signaling and small molecule inhibitors. Curr. Pharm. Des. 19, 634-664 (2013).
192. Nelson, W.J. & Nusse, R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303, 1483-1487 (2004).
193. Fujiwara, H., Tsutsui, K. & Morita, R. Multi-tasking epidermal stem cells: beyond epidermal maintenance. Dev. Growth Differ. 60, 531-541 (2018).
194. Chen, Y.A., et al. WW domain-containing proteins YAP and TAZ in the Hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis. Front. Oncol. 9, 60 (2019).
195. Owens, P., Han, G., Li, A.G. & Wang, X.J. The role of Smads in skin development. J. Invest. Dermatol. 128, 783-790 (2008).
196. Wu, N., Rollin, J., Masse, I., Lamartine, J. & Gidrol, X. p63 regulates human keratinocyte proliferation via MYC-regulated gene network and differentiation commitment through cell adhesion-related gene network. J. Biol. Chem. 287, 5627-5638 (2012).
197. Melino, G., et al. Itch: a HECT-type E3 ligase regulating immunity, skin and cancer. Cell Death Differ. 15, 1103-1112 (2008).
198. Petitjean, A., et al. Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with DeltaNp73. Carcinogenesis 29, 273-281 (2008).
199. Candi, E., et al. TAp63 and DeltaNp63 in cancer and epidermal development. Cell Cycle 6, 274-285 (2007).
200. Liu, P., Wang, M., Li, L. & Jin, T. Correlation between osteosarcoma and the expression of WWOX and p53. Oncol. Lett. 14, 4779-4783 (2017).
201. Jiang, Q.F., Tian, Y.W., Shen, Q., Xue, H.Z. & Li, K. SENP2 regulated the stability of β-catenin through WWOX in hepatocellular carcinoma cell. Tumour Biol. 35, 9677-9682 (2014).
202. Fuchs, E. & Raghavan, S. Getting under the skin of epidermal morphogenesis. Nat. Rev. Genet. 3, 199-209 (2002).
203. Asare, A., Levorse, J. & Fuchs, E. Coupling organelle inheritance with mitosis to balance growth and differentiation. Science 355(2017).
204. Jacobs, K.M., et al. GSK-3β: a bifunctional role in cell death pathways. Int. J. Cell Biol. 2012, 930710 (2012).
205. Kruglikov, I.L., Zhang, Z. & Scherer, P.E. The role of immature and mature adipocytes in hair cycling. Trends Endocrinol. Metab. 30, 93-105 (2019).
206. Romano, R.A., et al. DeltaNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 139, 772-782 (2012).
207. Lefterova, M.I., Haakonsson, A.K., Lazar, M.A. & Mandrup, S. PPARgamma and the global map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293-302 (2014).
208. Abu-Remaileh, M., et al. WWOX somatic ablation in skeletal muscles alters glucose metabolism. Mol. Metab. 22, 132-140 (2019).
209. Mai, S.H.C., et al. Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis. Intensive Care Med. Exp. 6, 20 (2018).

論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2022-09-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2022-09-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw