請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27481
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許世明 | |
dc.contributor.author | Yi-Hua Liao | en |
dc.contributor.author | 廖怡華 | zh_TW |
dc.date.accessioned | 2021-06-12T18:06:38Z | - |
dc.date.available | 2011-02-19 | |
dc.date.copyright | 2008-02-19 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-12-29 | |
dc.identifier.citation | Chapter I
Arevalo JC, Pereira DB, Yano H, Teng KK, Chao MV. Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. J Biol Chem 2006;281:1001-7. Arevalo JC, Yano H, Teng KK, Chao MV. A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J 2004;23:2358-68. Bedogni B, O'Neill MS, Welford SM, et al. Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. Cancer Res 2004;64:2552-60. Bevona C, Sober AJ. Melanoma incidence trends. Dermatol Clin 2002;20:589-95. Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J, Rivard N. MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 2000;79:355-69. Bulavin DV, Saito S, Hollander MC, et al. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 1999;18:6845-54. Carvalho H, Evelson P, Sigaud S, Gonzalez-Flecha B. Mitogen-activated protein kinases modulate H2O2-induced apoptosis in primary rat alveolar epithelial cells. J Cell Biochem 2004;92:502-13. Chang M, Arevalo JC, Chao MV. Ternary complex with Trk, p75, and an ankyrin-rich membrane spanning protein. J Neurosci Res 2004;78:186-92. Chang JW, Yeh KY, Wang CH, et al. Malignant melanoma in Taiwan: a prognostic study of 181 cases. Melanoma Res 2004;14:537-41. Chen YJ, Wu CY, Chen JT, Shen YL, Chen CC, Wang HC. Clinicopathologic analysis of malignant melanoma in Taiwan. J Am Acad Dermatol 1999;41:945-9. Christensen C, Guldberg P. Growth factors rescue cutaneous melanoma cells from apoptosis induced by knockdown of mutated (V600E) B-RAF. Oncogene 2005;24:6292-302. Chiari R, Hames G, Stroobant V, et al. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecule. Cancer Res 2000;60:4855-63. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev 2006;20:2149-82. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-47. Dhanwada KR, Dickens M, Neades R, Davis R, Pelling JC. Differential effects of UV-B and UV-C components of solar radiation on MAP kinase signal transduction pathways in epidermal keratinocytes. Oncogene 1995;11: 1947-53. Dhillon AP, Rode J. Patterns of staining for neurone specific enolase in benign and malignant melanocytic lesions of the skin. Diagn Histopathol 1982;5: 169-74. Easty DJ, Guthrie BA, Maung K, et al. Protein B61 as a new growth factor: expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression. Cancer Res 1995;55:2528-32. Easty DJ, Hill SP, Hsu MY, et al. Up-regulation of ephrin-A1 during melanoma progression. Int J Cancer 84:494-501. Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer Res 2003;63:8330-7. Fang D, Hallman J, Sangha N, et al. Expression of microtubule-associated protein 2 in benign and malignant melanocytes: implications for differentiation and progression of cutaneous melanoma. Am J Pathol 2001;158:2107-15. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281:1309-12. Herlyn M, Clark WH, Rodeck U, Mancianti ML, Jambrosic J, Koprowski H. Biology of tumor progression in human melanocytes. Lab Invest 1978;56:461-74. Holmstrom TH, Schmitz I, Soderstrom TS, et al. MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly. EMBO J 2000;19:5418-28. Huang C, Ma WY, Maxiner A, Sun Y, Dong Z. p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem 1999;274:12229-35. Iglesias T, Cabrera-Poch N, Mitchell MP, Naven TJP, Rozengurt E, Schiavo G. Identification and cloning of Kidins220, a novel neuronal substrate of protein kinase D. J Biol Chem 2000;275:40048-56. Innominato PF, Libbrecht L, van den Oord JJ. Expression of neurotrophins and their receptors in pigment cell lesions of the skin. J Pathol 2001;194:95-100. Kabbarah O, Chin L. Revealing the genomic heterogeneity of melanoma. Cancer Cell 2005;8:439-41. Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene 2004;23:6292-8. Khare VK, Albino AP, Reed JA. The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions. J Cutan Pathol 1998;25:2-10. Kong H, Boulter J, Weber JL, Lai C, Chao MV. An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors. J Neurosci 2001;21:176-85. Lammerding-Koppel M, Noda S, Blum A, Schaumburg-Lever G, Rassner G, Drews U. Immunohistochemical localization of muscarinic acetylcholine receptors in primary and metastatic malignant melanomas. J Cutan Pathol 1997;24:137-44. Langley RGB, et al: Clinical characteristics. In: Balch CM, Houghton AN, Sober AJ, Soong SJ, eds. Cutaneous Melanoma, 3rd ed. St Louis: Quality Medical, 1998, 81-101. Langley RGB, Barnhill RL, Mihm Jr. MC, Fitzpatrick TB, Sober AJ. Neoplasm: Cutaneous melanoma. In: Freedberg IM, Risen AZ, Wolff K, et al., eds. Dermatology in General Medicine. 5th ed. New York: McGraw-Hill, 1999, 1080-1116. Lee ML, Tomsu K, von Eschen KB. Duration of survival for disseminated malignant melanoma: Results of a meta-analysis. Melanoma Res 2000;10:81-92. Luk NM, Ho LC, Choi CL, Wong KH, Yu KH, Yeung WK. Clinicopathological features and prognostic factors of cutaneous melanoma among Hong Kong Chinese. Clin Exp Dermatol 2004;29:600-4. Luo S, Chen Y, Lai K-O, et al. Alpha-syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner. J Cell Biol 2005;169:813-24. Marchetti D, McCutcheon I, Ross M, Nicolson GL. Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human melanoma brain metastases. Int J Oncol 1995;7: 87–94. Marchetti D, McQuillan, David J, Spohn WC, Carson DD, Nicolson GL. Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Cancer Res 1996;56:2856-63. Melnikova VO, Bolshakov SV, Walker C, Ananthaswamy HN. Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines. Oncogene 2004;23:2347-56. Moan J, Dahlback A. The relationship between skin cancers, solar radiation and ozone depletion. Br J Cancer 1992;65:916-21. Ortonne JP. Photobiology and genetics of malignant melanoma. Br J Dermatol 2002;146 Suppl. 61:11-6. Prieto VG, McNutt NS, Lugo J, Reed JA. The intermediate filament peripherin is expressed in cutaneous melanocytic lesions. J Cutan Pathol 1997;24:145-50. Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003;63:756-9. Scaduto RC Jr, Grotyohann LW. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 1999;76:469-77. Shonukan O, Bagayogo I, McCrea P, Chao M, Hempstead B. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene 2003;22:3616-23. Soderstrom TS, Poukkula M, Holmstrom TH, Heiskanen KM, Eriksson JE. Mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in activated T cells abrogates TRAIL-induced apoptosis upstream of the mitochondrial amplification loop and caspase-8. J Immunol 2002;169:2851-60. Soltani MH, Pichardo R, Song Z, et al. Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma. Am J Pathol 2005;166:1841-50. Straume O, Akslen LA. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 2002;160:1009-19. Tada A, Pereira E, Beitner-Johnson D, Kavanagh R, Abdel-Malek ZA. Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. 2002;118:316-22. Vogt T, Stolz W, Welsh J, et al. Overexpression of Lerk-5/Eplg5 messenger RNA: a novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas. Clin Cancer Res 1998;4:791-7. Walch ET, Albino AP, Marchetti D. Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells. Int J Cancer 1999; 82:112-20. Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 2003;22:2869-81. Chapter II Aravind L, Iyer LM, Leipe DD, Koonin EV. A novel family of P-loop NTPases with an unusual phyletic distribution and transmembrane segments inserted within the NTPase domain. Genome Biol 2004;5:R30. Arevalo JC, Pereira DB, Yano H, Teng KK, Chao MV. Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. J Biol Chem 2006;281:1001-7. Arevalo JC, Yano H, Teng KK, Chao MV. A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J 2004;23:2358-68. Bamburg JR, Bray D, Chapman K. Assembly of microtubules at the tip of growing axons. Nature 1986; 321:788-790. Bracale A, Cesca F, Neubrand VE, Newsome TP, Way M, Schiavo G. Kidins220/ARMS is transported by a kinesin-1 based mechanism likely to be involved in neuronal differentiation. Mol Cell Biol 2007;18:142-52. Brown A. Axonal transport of membranous and nonmembranous cargoes: a unified perspective. J Cell Biol 2003;160:817-21. Cabrera-Poch N, Lucı´a Sa´nchez-Ruiloba L, Rodrıguez-Martınez M, Iglesias T. Lipid raft disruption triggers protein kinase C and Src-dependent protein kinase D activation and Kidins220 phosphorylation in neuronal cells. J Biol Chem 2004;279:28592–602. Chang M-S, Arevalo JC, Chao MV. Ternary complex with Trk, p75, and an ankyrin-rich membrane spanning protein. J Neurosci Res 2004;78:186-92. Cortes RY, Arevalo JC, Magby JP, Chao MV, Plummer MR. Developmental and activity-dependent regulation of ARMS/Kidins220 in cultured rat hippocampal neurons. Develop Neurobiol 2007;67:1687-98. Dent EW, Gertler FB. Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 2003;40:209-27. Goldstein LSB, Yang Z. Microtubule-based transport systems in neurons: the roles of kinesins and dyneins. Annu Rev Neurosci 2000;23:39-71. Gu C, Jan YN, Jan LY. A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels. Science 2003;301:646–9. Gu C, Zhou W, Puthenveedu MA, Xu M, Jan YN, Jan LY. The microtubule plus-end tracking protein EB1 is required for Kv1 voltage-gated K+ channel axonal targeting. Neuron 2006;52:803-16. Hirokawa N. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 1998;279:519-26. Hirokawa N. Stirring up development with the heterotrimeric kinesin KIF3. Traffic 2000;1:29-34. Iglesias T, Cabrera-Poch N, Mitchell MP, Naven TJP, Rozengurt E, Schiavo G. Identification and cloning of Kidins220, a novel neuronal substrate of protein kinase D. J Biol Chem 2000;275:40048-56. Imamura T, Huang J, Usui I, Satoh H, Bever J, Olefsky JM. Insulin-induced GLUT4 translocation involves protein kinase C-mediated functional coupling between Rab4 and the motor protein kinesin. Mol Cell Biol 2003;23:4892-900. Jimbo T, Kawasaki Y, Koyama R, et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nat Cell Biol 2002;4:323-27. Kondo S, Sato-Yoshitake R, Noda Y, et al. KIF3A is a new microtubule-based anterograde motor in the nerve axon. J Cell Biol 1994;125:1095-107. Kong H, Boulter J, Weber JL, Lai C, Chao MV. An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors. J Neurosci 2001;21:176-85. Lawrence CJ, Dawe RK, Christie KR, et al., A standardized kinesin nomenclature. J Cell Biol 2004;167:19-22. Le Bot N, Antony C, White J, Karsenti E, Vernos I. Role of xklp3, a subunit of the Xenopus kinesin II heterodimeric complex, in membrane transport between the endoplasmic reticulum and the Golgi apparatus. J Cell Biol 1998;143:1559-73. Liao YH, Hsu SM, Huang PH. Depletion of ARMS facilitates ARMS depletion facilitates UV irradiation–induced apoptotic cell death in melanoma. Cancer Res 2007;67:11547-56. Lin-Jones J, Parker E, Wu M, Knox BE, Burnside B. Disruption of Kinesin II function using a dominant negative-acting transgene in Xenopus laevis rods results in photoreceptor degeneration. Invest Ophthalmol Vis Sci 2003;44:3614-21. Marszalek JR, Liu X, Roberts EA, et al. Genetic evidence for selective transport of opsin and arrestin by Kinesin-II in mammalian photoreceptors. Cell 2000;102:175-87. Martenson C, Stone K, Reedy M, Sheetz M. Fast axonal transport is required for growth cone advance. Nature 1993;366:66-9. Meiri KF, Pfenninger KH, Willard MB. Growth associated protein, GAP-43, a polypeptide that is induced when neurons extend axons, is a component of growth cones and corresponds to pp46, a major polypeptide of a subcellular fraction enriched in growth cones. Proc Natl Acad Sci USA 1986;83:3537–41. Miki H, Okada Y, Hirokawa N. Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol 2005;15:467-76. Miki H, Setou M, Kaneshiro K, Hirokawa N. All kinesin superfamily protein, KIF, genes in mouse and human. Proc Natl Acad Sci USA 2001;98:7004-11. Muresan V, Abramson T, Lyass A, et al. KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles. Mol Biol Cell 1998;9:637-52. Muresan V, Lyass A, Schnapp BJ. The kinesin motor KIF3A is a component of the presynaptic ribbon in vertebrate photoreceptors. J Neurosci 1999;19:1027-37. Nagata K-i, Puls A, Futter C, et al. The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3. EMBO J 1998;17:149-58. Navone F, Consalez GG, Sardella M, et al. Expression of KIF3C kinesin during neural development and in vitro neuronal differentiation. J Neurochem 2001;77:741-53. Nishimura T, Kato K, Yamaguchi T, Fukata Y, Ohno S, Kaibuchi K. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nat Cell Biol 2004;6:328-34. Okada Y, Yamazaki H, Sekine-Aizawa Y, Hirokawa N. The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 1995;81:769–80. Ray K, Perez SE, Yang Z, et al. Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila. J Cell Biol 1999;147:507-18. Riol-Blanco LIT, Sanchez-Sanchez N, de la Rosa G, et al. The neuronal protein Kidins220 localizes in a raft compartment at the leading edge of motile immature dendritic cells. Eur J Immunol 2004;34:108-18. Sampo B, Kaech S, Kunz S, Banker G. Two distinct mechanisms target membrane proteins to the axonal surface. Neuron 2003;37:611–24. Sardella M, Navone F, Rocchi M, et al. KIF3C, a novel member of the kinesin superfamily: sequence, expression and mapping to human chromosome 2 at 2p23. Genomics 1998;47:405-8. Takeda S, Yamazaki H, Seog D-H, Kanai Y, Terada S, Hirokawa N. Kinesin superfamily protein 3 (KIF3) motor transports fodrin-associating vesicles important for neurite building. J Cell Biol 2000;148:1255-66. Tanaka Y, et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 1998;93:1147–58. Telford EAR, Wightman P, Leek J, Markham AF, Lench NJ, Bonthron DT. cDNA cloning, genomic organization, and chromosomal localization of a novel human gene that encodes a kinesin-related protein highly similar to mouse Kif3C. Biochem Biophys Res Commun 1998;242:407-12. Teng J, Rai T, Tanaka Y, et al. The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium. Nat Cell Biol 2005;7:474-82. Yamazaki H, Nakata T, Okada Y, Hirokawa N. Cloning and characterization of KAP3: A novel kinesin superfamily-associated protein of KIF3A/3B. Proc Natl Acad Sci USA 1996;93:8443-8. Yamazaki H, Nakata T, Okada Y, Hirokawa N. KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J Cell Biol 1995;130:1387-99. Yang Z, Goldstein LSB. Characterization of the KIF3C neural kinesin-like motor from mouse. Mol Biol Cell 1998;9:249-61. Yang Z, Roberts EA, Goldstein LSB. Functional analysis of mouse kinesin motor Kif3C. Mol Cell Biol 2001;21:5306-11. Yano H, Lee FS, Kong H, et al. Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor. J Neurosci 2001;21:125RC:1-7. Zhang Y-z, Moheban DB, Conway BR, Bhattacharyya A, Segal RA. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci 2000;20:5671-8. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27481 | - |
dc.description.abstract | ARMS (Ankyrin repeat-rich membrane spanning),又名Kidins220 (kinase D-interacting substrate of 220 kDa),是一個不隨演化改變,經細胞膜的蛋白分子,主要分布於神經組織及神經內分泌細胞。ARMS可和Trk 或Eph受器作用,是神經趨化因子(neurotrophin)/Trk及ephrin/Eph路徑的下游標的分子。ARMS因擁有多個蛋白質交互作用區域,可作為蛋白質交互作用時的建構平台,是一具有重要生物功能的分子,但許多ARMS扮演的生物角色仍未完全明瞭。
皮膚黑色素細胞癌是由黑色素細胞轉型產生,是由神經嵴衍生而來的惡性腫瘤,所以在黑色素細胞癌生成期,轉型細胞常會重新表現神經發育相關分子。因為神經趨化因子及ephrin調控的訊息傳遞和黑色素細胞癌腫瘤生成及進展有關,我們進而想探究ARMS是否參與黑色素細胞癌之腫瘤生成。我們發現ARMS在病患黑色素細胞癌檢體及人類黑色素細胞癌細胞株皆有過量表現。以RNA干擾方式降低ARMS在B16F0黑色素細胞癌細胞株的表現,會有意義降低癌細胞株的接觸獨立生長 (anchorage-independent growth),並抑制接種於SCID小鼠皮下之腫瘤生長。更重要的是,減少ARMS在黑色素細胞癌細胞的表現,會促進紫外線B光誘發之細胞凋亡,其作用機轉是透過MEK/ERK傳遞路徑之抑制,此路徑在多數亞洲人常見的肢端小痣型黑色素細胞癌並無自身活化之現象。我們的研究顯示ARMS單方面的過量表現,可藉由MEK/ERK路徑抑制壓力誘發之細胞凋亡,進而促進黑色素細胞癌的形成。 雖然最近的研究已使我們對ARMS在神經趨化因子引導的神經分化中扮演的角色有進一步了解,但有關ARMS如何被導引至神經突末端之機制仍為未知。 KIF3 (kinesin超家族蛋白質3; kinesin superfamily protein 3) 屬於異三聚體運輸蛋白(KIF3A-KIF3B-KAP或KIF3A-KIF3C-KAP3),負責膜性囊泡順式轉運(anterograde)的軸突傳導。由酵母菌雙雜交法、GST pull-down法、免疫共同沉澱法及免疫螢光共軛焦顯微鏡的研究顯示,ARMS的C端區段可個別和KIF3複合體的任一次單元(即KIF3A,KIF3B,KIF3C或KAP3A)作用。ARMS在神經突末端之定位需仰賴微管(microtubule),並需要ARMS的C端區段和有功能的KIF3複合體。除此之外,ARMS的 C端區段之過量表現或降低KIF3的表現及功能,皆會在接受神經生長因子刺激的PC12細胞中減少其神經突外長。由免疫分離及免疫電子顯微鏡的實驗顯示, ARMS和KIF3一同位於低電子密度、直徑約100至220 nm的囊泡上。我們的研究顯示ARMS位於膜性囊泡上,藉由KIF3複合體進行神經軸突傳導定位,此過程並可影響神經突生長。 | zh_TW |
dc.description.abstract | Ankyrin repeat-rich membrane spanning (ARMS), also known as kinase D-interacting substrate of 220 kDa (Kidins220), is an evolutionarily conserved transmembrane protein mainly expressed in the neural tissues and neuroendocrine cells. ARMS functions as a downstream and interacting molecule in the neurotrophin/Trk- and the ephrin/Eph- pathways, and it also acts as a scaffold molecule for protein-protein interaction because of the presence of multiple protein-protein interaction domains. Many of the biologic functions of ARMS remain unknown.
Malignant melanoma is a malignancy derived from neural crest. Because both neurotrophin- and ephrin-mediated signaling pathways have been demonstrated to be involved in melanoma tumorigenesis and progression, we thus wonder whether ARMS also participates in the carcinogenesis of malignant melanoma. We demonstrated overexpression of ARMS in human melanoma specimens and melanoma cell lines. Down-regulation of ARMS by RNA interference in B16F0 melanoma cells resulted in significant inhibition of anchorage-independent growth and restrictive growth of melanoma inoculated subcutaneously in SCID mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of MEK/ERK pathway, which is not constitutively activated in most cases of acral lentiginous melanoma, the melanoma subtype found mostly in Asians. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma Although recent studies have elucidated the role of ARMS in neurotrophin-induced neuronal differentiation, the mechanism how ARMS is targeted at neurite tips remains unknown. KIF3 (kinesin superfamily protein 3) is the heterotrimeric motor (KIF3A-KIF3B-KAP3 or KIF3A-KIF3C-KAP3) responsible for anterograde axonal transport for membranous vesicles. Here, we demonstrated a direct molecular interaction of the carboxy (C)-terminal region of ARMS with each subunit of KIF3 (KIF3A, KIF3B, KIF3C, or KAP3A, respectively) via yeast two-hybrid assay, GST pull-down, coimmunoprecipitation, and immunofluorescent confocal colocalization. Localization of ARMS at the tips of neurites was microtubule-dependent and required the presence of the C-terminal region of ARMS as well as functional KIF3 complexes. Furthermore, overexpression of the C-terminal region of ARMS or functionally knockdown of KIF3 impaired neurite outgrowth in nerve growth factor (NGF)-treated PC12 cells. Immunoisolation and immunoelectron microscopy demonstrated the colocalization of ARMS and KIF3 on the same electron-lucent vesicles ranging from 100 to 220 nm in diameter. Our study suggests that ARMS resides in membranous vesicles and relies on KIF3 complexes for their axonal targeting, a finding which plays an important role in neurite outgrowth. | en |
dc.description.provenance | Made available in DSpace on 2021-06-12T18:06:38Z (GMT). No. of bitstreams: 1 ntu-96-F90444007-1.pdf: 3008813 bytes, checksum: eb47c8ab37544c34d162b0a9692ba01d (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 口試委員會審定書…………………………………………………… i
誌謝 (Acknowledgement)…………………………………………… ii 中文摘要 (Chinese abstract)………………………………………iii 英文摘要 (English abstract)……………………………………… v 第一章 Overexpression of ankyrin repeat-rich membrane spanning (ARMS) proteins confers apoptosis resistance in malignant melanoma through MEK/ERK pathway……………………………………………………………….….. 1 第一節 摘要 (Abstract)……………………………………………….…….. 2 第二節 前言 (Introduction)…………………………………………….….... 4 第三節 材料與方法 (Materials and Methods)…………………………….. 10 第四節 實驗結果 (Results) …………………………………………….…. 17 第五節 討論 (Discussion)…………………………………………..……... 27 第六節 參考文獻 (Reference)...……………………………………..……. 33 第七節 附圖及說明 (Figures and figure legends)………………………… 39 第二章 Axonal targeting of ARMS-containing vesicles is mediated by KIF3 complex…………………………………………………………………. 50 第一節 摘要 (Abstract)……………………………………………………. 51 第二節 前言 (Introduction)………………………………………………... 53 第三節 材料與方法 (Materials and Methods)…………………………….. 57 第四節 實驗結果 (Results) …………………………………………….…. 65 第五節 討論 (Discussion)…………………………………………..……... 78 第六節 參考文獻 (Reference)………………………………………..…… 83 第七節 附圖及說明 (Figures and figure legends)………………………… 88 第三章 結語及展望 (Conclusions and perspective)…………………………….. 110 結語……………………………………………………………………... 111 展望……………………………………………………………………... 112 Figures Chapter 1 Fig. 1 ARMS is specifically overexpressed in malignant melanoma.…….. 39 Fig. 2 Depletion of ARMS by RNA interference prohibits anchorage -independent growth in vitro.……………………………………..... 41 Fig. 3 Melanoma growth is inhibited by ARMS-silencing in SCID mice.... 43 Fig. 4 Silencing of ARMS significantly increases caspase-dependent apoptosis after UVB treatment……………………………………………....... 44 Fig. 5 ERK pathway participates in ARMS-mediated apoptosis………...... 46 Fig. S1 Schematic representation of predicted topography of mouse ARMS..48 Chapter 2 Fig. 1 ARMS displayed a punctate distribution in neurons and was enriched at the tips of neurites based on intact microtubules…………………. 88 Fig. 2 Subcellular localization of ARMS.………………………………... 90 Fig. 3 ARMS interacted with KIF3A, KIF3B, KIF3C and KAP3A, respectively……………………………………………………..…. 92 Fig. 4 ARMS formed higher order of complexes with KIF3A, KIF3C and KAP3A……………………………………………………………. 94 Fig. 5 The C-terminal region of ARMS was required for its targeting to the tip of neurites……………………………………….………………….. 97 Fig. 6 Disruption of functional complex of KIF3A/KIF3C/KAP3A interfered with neurite outgrowth and the targeting of ARMS toward cell processes in NGF-treated PC12 cells……………………………………….......101 Fig. 7 ARMS and KAP3A colocalized to vesicles………………….……. 104 Fig. 8 TrkB was associated with ARMS and KAP3A in mouse brain……... 107 Fig S1 Structure of heterotrimeric KIF3 complex………………………..…108 Tables Chapter 1 Table 1 ARMS expression in normal skin, benign nevi, primary cutaneous melanoma, and metastatic melanoma………….………………… 49 Chapter 2 Table 1 Family, subfamily and member names of kinesin superfamily proteins involved in neuronal transport………….……………………..…... 109 | |
dc.language.iso | en | |
dc.title | 探討ARMS的生物功能:(I)參與黑色素細胞癌腫瘤生成機制之探討及(II)KIF3導引之神經軸突運送及神經突生長 | zh_TW |
dc.title | Characterization of the biological functions of ARMS (ankyrin repeat-rich membrane spanning) in melanoma tumorigenesis and KIF3-mediated axonal transport and neurite outgrowth | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 李芳仁,紀秀華,郭明良,黃佩欣(Pei-Hsin Huang),鄭安理,錢宗良 | |
dc.subject.keyword | ARMS,黑色素細胞癌,細胞凋亡,MEK/ERK路徑,KIF3,神經軸突傳導,神經突生長, | zh_TW |
dc.subject.keyword | ARMS,melanoma,apoptosis,MEK/ERK pathway,KIF3,axonal transport,neuronal outgrowth, | en |
dc.relation.page | 113 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-12-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 病理學研究所 | zh_TW |
顯示於系所單位: | 病理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-96-1.pdf 目前未授權公開取用 | 2.94 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。