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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
dc.contributor.author | Won-Jing Wang | en |
dc.contributor.author | 王琬菁 | zh_TW |
dc.date.accessioned | 2021-06-13T17:26:20Z | - |
dc.date.available | 2005-02-25 | |
dc.date.copyright | 2005-02-25 | |
dc.date.issued | 2005 | |
dc.date.submitted | 2005-01-19 | |
dc.identifier.citation | Abraham,M.C. and Shaham,S. (2004). Death without caspases, caspases without death. Trends Cell Biol. 14, 184-193. Almeida,E.A., Ilic,D., Han,Q., Hauck,C.R., Jin,F., Kawakatsu,H., Schlaepfer,D.D., and Damsky,C.H. (2000). Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J. Cell Biol. 149, 741-754. Alonso,A., Sasin,J., Bottini,N., Friedberg,I., Friedberg,I., Osterman,A., Godzik,A., Hunter,T., Dixon,J., and Mustelin,T. (2004). Protein tyrosine phosphatases in the human genome. Cell 117, 699-711. Andersen,J.N., Mortensen,O.H., Peters,G.H., Drake,P.G., Iversen,L.F., Olsen,O.H., Jansen,P.G., Andersen,H.S., Tonks,N.K., and Moller,N.P. (2001). Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell Biol. 21, 7117-7136. Arnoult,D., Gaume,B., Karbowski,M., Sharpe,J.C., Cecconi,F., and Youle,R.J. (2003). Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO J. 22, 4385-4399. Aznar,S., Fernandez-Valeron,P., Espina,C., and Lacal,J.C. (2004). Rho GTPases: potential candidates for anticancer therapy. Cancer Lett. 206, 181-191. Barr,P.J. and Tomei,L.D. (1994). Apoptosis and its role in human disease. Biotechnology (N. Y. ) 12, 487-493. Bennett,M., Macdonald,K., Chan,S.W., Luzio,J.P., Simari,R., and Weissberg,P. (1998). Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282, 290-293. Bevan,P. (2001). Insulin signalling. J. Cell Sci. 114, 1429-1430. Bialik,S., Bresnick,A.R., and Kimchi,A. (2004). DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation. Cell Death. Differ. 11, 631-644. Blaukat,A., Ivankovic-Dikic,I., Gronroos,E., Dolfi,F., Tokiwa,G., Vuori,K., and Dikic,I. (1999). Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades. J. Biol. Chem. 274, 14893-14901. Bockholt,S.M. and Burridge,K. (1993). Cell spreading on extracellular matrix proteins induces tyrosine phosphorylation of tensin. J. Biol. Chem. 268, 14565-14567. Bodary,S.C. and McLean,J.W. (1990). The integrin beta 1 subunit associates with the vitronectin receptor alpha v subunit to form a novel vitronectin receptor in a human embryonic kidney cell line. J. Biol. Chem. 265, 5938-5941.
Bong,Y.S., Park,Y.H., Lee,H.S., Mood,K., Ishimura,A., and Daar,I.O. (2004). Tyr-298 in ephrinB1 is critical for an interaction with the Grb4 adaptor protein. Biochem. J. 377, 499-507. Boudreau,N., Sympson,C.J., Werb,Z., and Bissell,M.J. (1995). Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267, 891-893. Bridgham,J.T., Wilder,J.A., Hollocher,H., and Johnson,A.L. (2003). All in the family: evolutionary and functional relationships among death receptors. Cell Death. Differ. 10, 19-25. Brooks,P.C., Montgomery,A.M., Rosenfeld,M., Reisfeld,R.A., Hu,T., Klier,G., and Cheresh,D.A. (1994). Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157-1164. Burridge,K., Turner,C.E., and Romer,L.H. (1992). Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J. Cell Biol. 119, 893-903. Calderwood,D.A., Zent,R., Grant,R., Rees,D.J., Hynes,R.O., and Ginsberg,M.H. (1999). The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28071-28074. Cardone,M.H., Roy,N., Stennicke,H.R., Salvesen,G.S., Franke,T.F., Stanbridge,E., Frisch,S., and Reed,J.C. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318-1321. Cary,L.A. and Guan,J.L. (1999). Focal adhesion kinase in integrin-mediated signaling. Front Biosci. 4, D102-D113. Chan,P.Y., Kanner,S.B., Whitney,G., and Aruffo,A. (1994). A transmembrane-anchored chimeric focal adhesion kinase is constitutively activated and phosphorylated at tyrosine residues identical to pp125FAK. J. Biol. Chem. 269, 20567-20574. Chen,C.H., Wang,W.J., Kuo,J.C., Tsai,H.C., Lin,J.R., Chang,Z.F., and Chen,R.H. (2004). Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J. Chipuk,J.E., Kuwana,T., Bouchier-Hayes,L., Droin,N.M., Newmeyer,D.D., Schuler,M., and Green,D.R. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010-1014. Chipuk,J.E., Maurer,U., Green,D.R., and Schuler,M. (2003). Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4, 371-381. Clark,E.A. and Brugge,J.S. (1995). Integrins and signal transduction pathways: the road taken. Science 268, 233-239. Cohen,O., Feinstein,E., and Kimchi,A. (1997). DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J. 16, 998-1008. Cohen,O., Inbal,B., Kissil,J.L., Raveh,T., Berissi,H., Spivak-Kroizaman,T., Feinstein,E., and Kimchi,A. (1999). DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J. Cell Biol. 146, 141-148. Cohen,O. and Kimchi,A. (2001). DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death. Differ. 8, 6-15. Cohen,P. (2000). The regulation of protein function by multisite phosphorylation--a 25 year update. Trends Biochem. Sci. 25, 596-601. Conradt,B. and Horvitz,H.R. (1998). The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93, 519-529. Coucouvanis,E. and Martin,G.R. (1995). Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell 83, 279-287. Davis,S., Lu,M.L., Lo,S.H., Lin,S., Butler,J.A., Druker,B.J., Roberts,T.M., An,Q., and Chen,L.B. (1991). Presence of an SH2 domain in the actin-binding protein tensin. Science 252, 712-715. Debant,A., Serra-Pages,C., Seipel,K., O'Brien,S., Tang,M., Park,S.H., and Streuli,M. (1996). The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc. Natl. Acad. Sci. U. S. A 93, 5466-5471. Debnath,J., Mills,K.R., Collins,N.L., Reginato,M.J., Muthuswamy,S.K., and Brugge,J.S. (2002). The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell 111, 29-40. Deiss,L.P., Feinstein,E., Berissi,H., Cohen,O., and Kimchi,A. (1995). Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 9, 15-30. DeLeo,A.B., Jay,G., Appella,E., Dubois,G.C., Law,L.W., and Old,L.J. (1979). Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc. Natl. Acad. Sci. U. S. A 76, 2420-2424. Denu,J.M., Stuckey,J.A., Saper,M.A., and Dixon,J.E. (1996). Form and function in protein dephosphorylation. Cell 87, 361-364. Di,M.T., Mueller,F., Fenzi,G., Rossi,G., Bifulco,M., Marzano,L.A., and Vitale,M. (2000). Serum withdrawal-induced apoptosis in thyroid cells is caused by loss of fibronectin-integrin interaction. J. Clin. Endocrinol. Metab 85, 1188-1193. Ding,H.F., Lin,Y.L., McGill,G., Juo,P., Zhu,H., Blenis,J., Yuan,J., and Fisher,D.E. (2000). Essential role for caspase-8 in transcription-independent apoptosis triggered by p53. J. Biol. Chem. 275, 38905-38911. Du,C., Fang,M., Li,Y., Li,L., and Wang,X. (2000). Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33-42. Dumont,P., Leu,J.I., Della,P.A., III, George,D.L., and Murphy,M. (2003). The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet. 33, 357-365. Earnshaw,W.C. (1999). Apoptosis. A cellular poison cupboard. Nature 397, 387, 389. Earnshaw,W.C., Martins,L.M., and Kaufmann,S.H. (1999). Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383-424. Farmer,G., Colgan,J., Nakatani,Y., Manley,J.L., and Prives,C. (1996). Functional interaction between p53, the TATA-binding protein (TBP), andTBP-associated factors in vivo. Mol. Cell Biol. 16, 4295-4304. Fauman,E.B. and Saper,M.A. (1996). Structure and function of the protein tyrosine phosphatases. Trends Biochem. Sci. 21, 413-417. Flint,A.J., Tiganis,T., Barford,D., and Tonks,N.K. (1997). Development of 'substrate-trapping' mutants to identify physiological substrates of protein tyrosine phosphatases. Proc. Natl. Acad. Sci. U. S. A 94, 1680-1685. Fridman,J.S. and Lowe,S.W. (2003). Control of apoptosis by p53. Oncogene 22, 9030-9040. Frisch,S.M. (1999). Evidence for a function of death-receptor-related, death-domain-containing proteins in anoikis. Curr. Biol. 9, 1047-1049. Frisch,S.M. and Francis,H. (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619-626. Frisch,S.M. and Ruoslahti,E. (1997). Integrins and anoikis. Curr. Opin. Cell Biol. 9, 701-706. Frisch,S.M. and Screaton,R.A. (2001). Anoikis mechanisms. Curr. Opin. Cell Biol. 13, 555-562. Frisch,S.M., Vuori,K., Ruoslahti,E., and Chan-Hui,P.Y. (1996). Control of adhesion-dependent cell survival by focal adhesion kinase. J. Cell Biol. 134, 793-799. Gailit,J. and Ruoslahti,E. (1988). Regulation of the fibronectin receptor affinity by divalent cations. J. Biol. Chem. 263, 12927-12932. Galic,S., Hauser,C., Kahn,B.B., Haj,F.G., Neel,B.G., Tonks,N.K., and Tiganis,T. (2005). Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP. Mol. Cell Biol. 25, 819-829. Garcia-Alvarez,B., de Pereda,J.M., Calderwood,D.A., Ulmer,T.S., Critchley,D., Campbell,I.D., Ginsberg,M.H., and Liddington,R.C. (2003). Structural determinants of integrin recognition by talin. Mol. Cell 11, 49-58. Garton,A.J., Flint,A.J., and Tonks,N.K. (1996). Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST. Mol. Cell Biol. 16, 6408-6418. Giancotti,F.G. and Ruoslahti,E. (1999). Integrin signaling. Science 285, 1028-1032. Giancotti,F.G. and Tarone,G. (2003). Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu. Rev. Cell Dev. Biol. 19, 173-206. Gilmore,A.P., Metcalfe,A.D., Romer,L.H., and Streuli,C.H. (2000). Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J. Cell Biol. 149, 431-446. Ginsberg,M.H., Du,X., and Plow,E.F. (1992). Inside-out integrin signalling. Curr. Opin. Cell Biol. 4, 766-771. Ginsberg,M.H., Yaspan,B., Forsyth,J., Ulmer,T.S., Campbell,I.D., and Slepak,M. (2001). A membrane-distal segment of the integrin alpha IIb cytoplasmic domain regulates integrin activation. J. Biol. Chem. 276, 22514-22521. Goncharova,E., Goncharov,D., Noonan,D., and Krymskaya,V.P. (2004). TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. J. Cell Biol. 167, 1171-1182. Gozuacik,D. and Kimchi,A. (2004). Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23, 2891-2906. Greenwood,J.A. and Murphy-Ullrich,J.E. (1998). Signaling of de-adhesion in cellular regulation and motility. Microsc. Res. Tech. 43, 420-432. Grossmann,J., Mohr,S., Lapentina,E.G., Fiocchi,C., and Levine,A.D. (1998). Sequential and rapid activation of select caspases during apoptosis of normal intestinal epithelial cells. Am. J. Physiol 274, G1117-G1124. Grossmann,J., Walther,K., Artinger,M., Kiessling,S., and Scholmerich,J. (2001). Apoptotic signaling during initiation of detachment-induced apoptosis ('anoikis') of primary human intestinal epithelial cells. Cell Growth Differ. 12, 147-155. Guan,J.L. (1997). Focal adhesion kinase in integrin signaling. Matrix Biol. 16, 195-200. Haldar,S., Negrini,M., Monne,M., Sabbioni,S., and Croce,C.M. (1994). Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 54, 2095-2097. Hengartner,M.O. and Horvitz,H.R. (1994). C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665-676. Hoffman,W.H., Biade,S., Zilfou,J.T., Chen,J., and Murphy,M. (2002). Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247-3257. Hood,J.D., Bednarski,M., Frausto,R., Guccione,S., Reisfeld,R.A., Xiang,R., and Cheresh,D.A. (2002). Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404-2407. Hughes,P.E. and Pfaff,M. (1998). Integrin affinity modulation. Trends Cell Biol. 8, 359-364. Humphries,M.J. (2000). Integrin structure. Biochem. Soc. Trans. 28, 311-339. Hungerford,J.E., Compton,M.T., Matter,M.L., Hoffstrom,B.G., and Otey,C.A. (1996). Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J. Cell Biol. 135, 1383-1390. Hunter,T. (2000). Signaling--2000 and beyond. Cell 100, 113-127. Hunter,T. and Sefton,B.M. (1980). Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl. Acad. Sci. U. S. A 77, 1311-1315. Hussain,S.P. and Harris,C.C. (1998). Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res. 58, 4023-4037. Hynes,R.O. (1992). Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69, 11-25. Hynes,R.O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673-687. Hynes,R.O. and Zhao,Q. (2000). The evolution of cell adhesion. J. Cell Biol. 150, F89-F96. Ilic,D., Almeida,E.A., Schlaepfer,D.D., Dazin,P., Aizawa,S., and Damsky,C.H. (1998). Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J. Cell Biol. 143, 547-560. Ilic,D., Damsky,C.H., and Yamamoto,T. (1997). Focal adhesion kinase: at the crossroads of signal transduction 2. J. Cell Sci. 110 ( Pt 4), 401-407. Inbal,B., Bialik,S., Sabanay,I., Shani,G., and Kimchi,A. (2002). DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J. Cell Biol. 157, 455-468. Inbal,B., Cohen,O., Polak-Charcon,S., Kopolovic,J., Vadai,E., Eisenbach,L., and Kimchi,A. (1997). DAP kinase links the control of apoptosis to metastasis. Nature 390, 180-184. Inbal,B., Shani,G., Cohen,O., Kissil,J.L., and Kimchi,A. (2000). Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol. Cell Biol. 20, 1044-1054. Jacobson,M.D., Weil,M., and Raff,M.C. (1997). Programmed cell death in animal development. Cell 88, 347-354. Jang,C.W., Chen,C.H., Chen,C.C., Chen,J.Y., Su,Y.H., and Chen,R.H. (2002). TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat. Cell Biol. 4, 51-58. Jost,M., Huggett,T.M., Kari,C., and Rodeck,U. (2001). Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway. Mol. Biol. Cell 12, 1519-1527. Kannan,K., Kaminski,N., Rechavi,G., Jakob-Hirsch,J., Amariglio,N., and Givol,D. (2001). DNA microarray analysis of genes involved in p53 mediated apoptosis: activation of Apaf-1. Oncogene 20, 3449-3455. Kawai,T., Matsumoto,M., Takeda,K., Sanjo,H., and Akira,S. (1998). ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol. Cell Biol. 18, 1642-1651. Kellie,S., Craggs,G., Bird,I.N., and Jones,G.E. (2004). The tyrosine phosphatase DEP-1 induces cytoskeletal rearrangements, aberrant cell-substratum interactions and a reduction in cell proliferation. J. Cell Sci. 117, 609-618. Kerr,J.F., Wyllie,A.H., and Currie,A.R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239-257. Khwaja,A., Rodriguez-Viciana,P., Wennstrom,S., Warne,P.H., and Downward,J. (1997). Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16, 2783-2793. Kinbara,K., Goldfinger,L.E., Hansen,M., Chou,F.L., and Ginsberg,M.H. (2003). Ras GTPases: integrins' friends or foes? Nat. Rev. Mol. Cell Biol. 4, 767-776. Kirsch,K., Kensinger,M., Hanafusa,H., and August,A. (2002). A p130Cas tyrosine phosphorylated substrate domain decoy disrupts v-crk signaling. BMC. Cell Biol. 3, 18. Ko,L.J. and Prives,C. (1996). p53: puzzle and paradigm. Genes Dev. 10, 1054-1072. Kogel,D., Reimertz,C., Mech,P., Poppe,M., Fruhwald,M.C., Engemann,H., Scheidtmann,K.H., and Prehn,J.H. (2001). Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway. Br. J. Cancer 85, 1801-1808. Koumenis,C., Alarcon,R., Hammond,E., Sutphin,P., Hoffman,W., Murphy,M., Derr,J., Taya,Y., Lowe,S.W., Kastan,M., and Giaccia,A. (2001). Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol. Cell Biol. 21, 1297-1310. Krueger,N.X., Van,V.D., Wan,H.I., Gelbart,W.M., Goodman,C.S., and Saito,H. (1996). The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell 84, 611-622. Kuo,J.C., Lin,J.R., Staddon,J.M., Hosoya,H., and Chen,R.H. (2003). Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase. J. Cell Sci. 116, 4777-4790. Lanier,L.M., Gates,M.A., Witke,W., Menzies,A.S., Wehman,A.M., Macklis,J.D., Kwiatkowski,D., Soriano,P., and Gertler,F.B. (1999). Mena is required for neurulation and commissure formation. Neuron 22, 313-325. Leu,J.I., Dumont,P., Hafey,M., Murphy,M.E., and George,D.L. (2004). Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol. 6, 443-450. Li,G., Fridman,R., and Kim,H.R. (1999). Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells 1. Cancer Res. 59, 6267-6275. Li,H., Zhu,H., Xu,C.J., and Yuan,J. (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501. Li,L.Y., Luo,X., and Wang,X. (2001). Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412, 95-99. Lim,M.L., Lum,M.G., Hansen,T.M., Roucou,X., and Nagley,P. (2002). On the release of cytochrome c from mitochondria during cell death signaling. J. Biomed. Sci. 9, 488-506. Liu,X., Kim,C.N., Yang,J., Jemmerson,R., and Wang,X. (1996). Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147-157. Lo,S.H., Janmey,P.A., Hartwig,J.H., and Chen,L.B. (1994). Interactions of tensin with actin and identification of its three distinct actin-binding domains. J. Cell Biol. 125, 1067-1075. Lockshin,R.A. and Zakeri,Z. (2004a). Apoptosis, autophagy, and more. Int. J. Biochem. Cell Biol. 36, 2405-2419. Lockshin,R.A. and Zakeri,Z. (2004b). Caspase-independent cell death? Oncogene 23, 2766-2773. Longo,F.M., Martignetti,J.A., Le Beau,J.M., Zhang,J.S., Barnes,J.P., and Brosius,J. (1993). Leukocyte common antigen-related receptor-linked tyrosine phosphatase. Regulation of mRNA expression. J. Biol. Chem. 268, 26503-26511. Luo,X., Budihardjo,I., Zou,H., Slaughter,C., and Wang,X. (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481-490. MacLachlan,T.K. and El-Deiry,W.S. (2002). Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl. Acad. Sci. U. S. A 99, 9492-9497. Maecker,H.L., Koumenis,C., and Giaccia,A.J. (2000). p53 promotes selection for Fas-mediated apoptotic resistance. Cancer Res. 60, 4638-4644. Marti,A., Luo,Z., Cunningham,C., Ohta,Y., Hartwig,J., Stossel,T.P., Kyriakis,J.M., and Avruch,J. (1997). Actin-binding protein-280 binds the stress-activated protein kinase (SAPK) activator SEK-1 and is required for tumor necrosis factor-alpha activation of SAPK in melanoma cells. J. Biol. Chem. 272, 2620-2628. McDonnell,T.J. and Korsmeyer,S.J. (1991). Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 349, 254-256. Meredith,J.E., Jr., Fazeli,B., and Schwartz,M.A. (1993). The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4, 953-961. Mihara,M., Erster,S., Zaika,A., Petrenko,O., Chittenden,T., Pancoska,P., and Moll,U.M. (2003). p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577-590. Mills,K.R., Reginato,M., Debnath,J., Queenan,B., and Brugge,J.S. (2004). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl. Acad. Sci. U. S. A 101, 3438-3443. Miyamoto,S., Teramoto,H., Gutkind,J.S., and Yamada,K.M. (1996). Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J. Cell Biol. 135, 1633-1642. Miyashita,T., Krajewski,S., Krajewska,M., Wang,H.G., Lin,H.K., Liebermann,D.A., Hoffman,B., and Reed,J.C. (1994). Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9, 1799-1805. Mizushima,N., Ohsumi,Y., and Yoshimori,T. (2002). Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421-429. Mizushima,N., Yoshimori,T., and Ohsumi,Y. (2003). Role of the Apg12 conjugation system in mammalian autophagy. Int. J. Biochem. Cell Biol. 35, 553-561. Moroni,M.C., Hickman,E.S., Denchi,E.L., Caprara,G., Colli,E., Cecconi,F., Muller,H., and Helin,K. (2001). Apaf-1 is a transcriptional target for E2F and p53. Nat. Cell Biol. 3, 552-558. Mould,A.P., Akiyama,S.K., and Humphries,M.J. (1995). Regulation of integrin alpha 5 beta 1-fibronectin interactions by divalent cations. Evidence for distinct classes of binding sites for Mn2+, Mg2+, and Ca2+. J. Biol. Chem. 270, 26270-26277. Mould,A.P., Symonds,E.J., Buckley,P.A., Grossmann,J.G., McEwan,P.A., Barton,S.J., Askari,J.A., Craig,S.E., Bella,J., and Humphries,M.J. (2003). Structure of an integrin-ligand complex deduced from solution x-ray scattering and site-directed mutagenesis. J. Biol. Chem. 278, 39993-39999. Muller,M., Wilder,S., Bannasch,D., Israeli,D., Lehlbach,K., Li-Weber,M., Friedman,S.L., Galle,P.R., Stremmel,W., Oren,M., and Krammer,P.H. (1998). p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033-2045. Murphy,M., Ahn,J., Walker,K.K., Hoffman,W.H., Evans,R.M., Levine,A.J., and George,D.L. (1999). Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490-2501. Murphy,M., Hinman,A., and Levine,A.J. (1996). Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Genes Dev. 10, 2971-2980. Murphy-Ullrich,J.E. (2001). The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? J. Clin. Invest 107, 785-790. Muzio,M., Chinnaiyan,A.M., Kischkel,F.C., O'Rourke,K., Shevchenko,A., Ni,J., Scaffidi,C., Bretz,J.D., Zhang,M., Gentz,R., Mann,M., Krammer,P.H., Peter,M.E., and Dixit,V.M. (1996). FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell 85, 817-827. Nakano,K. and Vousden,K.H. (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683-694. Neel,B.G. and Tonks,N.K. (1997). Protein tyrosine phosphatases in signal transduction. Curr. Opin. Cell Biol. 9, 193-204. ngers-Loustau,A., Cote,J.F., Charest,A., Dowbenko,D., Spencer,S., Lasky,L.A., and Tremblay,M.L. (1999). Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts. J. Cell Biol. 144, 1019-1031. Ni,H., Li,A., Simonsen,N., and Wilkins,J.A. (1998). Integrin activation by dithiothreitol or Mn2+ induces a ligand-occupied conformation and exposure of a novel NH2-terminal regulatory site on the beta1 integrin chain. J. Biol. Chem. 273, 7981-7987. Noda,T., Suzuki,K., and Ohsumi,Y. (2002). Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol. 12, 231-235. O'Brien,V., Frisch,S.M., and Juliano,R.L. (1996). Expression of the integrin alpha 5 subunit in HT29 colon carcinoma cells suppresses apoptosis triggered by serum deprivation. Exp. Cell Res. 224, 208-213. O'Toole,T.E., Katagiri,Y., Faull,R.J., Peter,K., Tamura,R., Quaranta,V., Loftus,J.C., Shattil,S.J., and Ginsberg,M.H. (1994). Integrin cytoplasmic domains mediate inside-out signal transduction. J. Cell Biol. 124, 1047-1059. Oda,E., Ohki,R., Murasawa,H., Nemoto,J., Shibue,T., Yamashita,T., Tokino,T., Taniguchi,T., and Tanaka,N. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053-1058. Ohsumi,Y. (2001a). Molecular dissection of autophagy: two ubiquitin-like systems. Nat. Rev. Mol. Cell Biol. 2, 211-216. Ohsumi,Y. (2001b). [Molecular mechanism of bulk protein degradation in lysosome/vacuole]. Tanpakushitsu Kakusan Koso 46, 1710-1716. Ostman,A. and Bohmer,F.D. (2001). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 11, 258-266. Otto,I.M., Raabe,T., Rennefahrt,U.E., Bork,P., Rapp,U.R., and Kerkhoff,E. (2000). The p150-Spir protein provides a link between c-Jun N-terminal kinase function and actin reorganization. Curr. Biol. 10, 345-348. Owen-Schaub,L.B., Zhang,W., Cusack,J.C., Angelo,L.S., Santee,S.M., Fujiwara,T., Roth,J.A., Deisseroth,A.B., Zhang,W.W., Kruzel,E., and . (1995). Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol. Cell Biol. 15, 3032-3040. Pankov,R. and Yamada,K.M. (2002). Fibronectin at a glance. J. Cell Sci. 115, 3861-3863. Pannifer,A.D., Flint,A.J., Tonks,N.K., and Barford,D. (1998). Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by x-ray crystallography. J. Biol. Chem. 273, 10454-10462. Paul,S. and Lombroso,P.J. (2003). Receptor and nonreceptor protein tyrosine phosphatases in the nervous system. Cell Mol. Life Sci. 60, 2465-2482. Pelled,D., Raveh,T., Riebeling,C., Fridkin,M., Berissi,H., Futerman,A.H., and Kimchi,A. (2002). Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons. J. Biol. Chem. 277, 1957-1961. Persad,S., Attwell,S., Gray,V., Mawji,N., Deng,J.T., Leung,D., Yan,J., Sanghera,J., Walsh,M.P., and Dedhar,S. (2001). Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem. 276, 27462-27469. Petch,L.A., Bockholt,S.M., Bouton,A., Parsons,J.T., and Burridge,K. (1995). Adhesion-induced tyrosine phosphorylation of the p130 src substrate. J. Cell Sci. 108 ( Pt 4), 1371-1379. Pils,B. and Schultz,J. (2004). Evolution of the multifunctional protein tyrosine phosphatase family. Mol. Biol. Evol. 21, 625-631. Playford,M.P. and Schaller,M.D. (2004). The interplay between Src and integrins in normal and tumor biology. Oncogene 23, 7928-7946. Polster,B.M. and Fiskum,G. (2004). Mitochondrial mechanisms of neural cell apoptosis. J. Neurochem. 90, 1281-1289. Polte,T.R., Eichler,G.S., Wang,N., and Ingber,D.E. (2004). Extracellular matrix controls myosin light chain phosphorylation and cell contractility through modulation of cell shape and cytoskeletal prestress. Am. J. Physiol Cell Physiol 286, C518-C528. Puthalakath,H., Huang,D.C., O'Reilly,L.A., King,S.M., and Strasser,A. (1999). The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287-296. Puthalakath,H., Villunger,A., O'Reilly,L.A., Beaumont,J.G., Coultas,L., Cheney,R.E., Huang,D.C., and Strasser,A. (2001). Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293, 1829-1832. Raveh,T., Berissi,H., Eisenstein,M., Spivak,T., and Kimchi,A. (2000). A functional genetic screen identifies regions at the C-terminal tail and death-domain of death-associated protein kinase that are critical for its proapoptotic activity. Proc. Natl. Acad. Sci. U. S. A 97, 1572-1577. Raveh,T., Droguett,G., Horwitz,M.S., DePinho,R.A., and Kimchi,A. (2001). DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat. Cell Biol. 3, 1-7. Raveh,T. and Kimchi,A. (2001). DAP kinase-a proapoptotic gene that functions as a tumor suppressor. Exp. Cell Res. 264, 185-192. Re,F., Zanetti,A., Sironi,M., Polentarutti,N., Lanfrancone,L., Dejana,E., and Colotta,F. (1994). Inhibition of anchorage-dependent cell spreading triggers apoptosis in cultured human endothelial cells. J. Cell Biol. 127, 537-546. Reggiori,F. and Klionsky,D.J. (2002). Autophagy in the eukaryotic cell. Eukaryot. Cell 1, 11-21. Renshaw,M.W., Ren,X.D., and Schwartz,M.A. (1997). Growth factor activation of MAP kinase requires cell adhesion. EMBO J. 16, 5592-5599. Riedl,S.J. and Shi,Y. (2004). Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell Biol. 5, 897-907. Robles,A.I., Bemmels,N.A., Foraker,A.B., and Harris,C.C. (2001). APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer Res. 61, 6660-6664. Romsicki,Y., Scapin,G., Beaulieu-Audy,V., Patel,S., Becker,J.W., Kennedy,B.P., and sante-Appiah,E. (2003). Functional characterization and crystal structure of the C215D mutant of protein-tyrosine phosphatase-1B. J. Biol. Chem. 278, 29009-29015. Ruoslahti,E. and Pierschbacher,M.D. (1987). New perspectives in cell adhesion: RGD and integrins. Science 238, 491-497. Rytomaa,M., Martins,L.M., and Downward,J. (1999). Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr. Biol. 9, 1043-1046. Sage,E.H. and Bornstein,P. (1991). Extracellular proteins that modulate cell-matrix interactions. SPARC, tenascin, and thrombospondin. J. Biol. Chem. 266, 14831-14834. Sakagami,H. and Kondo,H. (1997). Molecular cloning and developmental expression of a rat homologue of death-associated protein kinase in the nervous system. Brain Res. Mol. Brain Res. 52, 249-256. Samali,A., Cai,J., Zhivotovsky,B., Jones,D.P., and Orrenius,S. (1999). Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J. 18, 2040-2048. Sanjo,H., Kawai,T., and Akira,S. (1998). DRAKs, novel serine/threonine kinases related to death-associated protein kinase that trigger apoptosis. J. Biol. Chem. 273, 29066-29071. sante-Appiah,E. and Kennedy,B.P. (2003). Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am. J. Physiol Endocrinol. Metab 284, E663-E670. Sax,J.K., Fei,P., Murphy,M.E., Bernhard,E., Korsmeyer,S.J., and El-Deiry,W.S. (2002). BID regulation by p53 contributes to chemosensitivity. Nat. Cell Biol. 4, 842-849. Schoenwaelder,S.M. and Burridge,K. (1999). Bidirectional signaling between the cytoskeleton and integrins. Curr. Opin. Cell Biol. 11, 274-286. Schuler,M., Bossy-Wetzel,E., Goldstein,J.C., Fitzgerald,P., and Green,D.R. (2000). p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J. Biol. Chem. 275, 7337-7342. Schuler,M. and Green,D.R. (2001). Mechanisms of p53-dependent apoptosis. Biochem. Soc. Trans. 29, 684-688. Schwartz,M.A. (2001). Integrin signaling revisited. Trends Cell Biol. 11, 466-470. Sedgwick,S.G. and Smerdon,S.J. (1999). The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem. Sci. 24, 311-316. Serra-Pages,C., Kedersha,N.L., Fazikas,L., Medley,Q., Debant,A., and Streuli,M. (1995). The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 14, 2827-2838. Seto,E., Usheva,A., Zambetti,G.P., Momand,J., Horikoshi,N., Weinmann,R., Levine,A.J., and Shenk,T. (1992). Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc. Natl. Acad. Sci. U. S. A 89, 12028-12032. Shi,Y. (2004). Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci. 13, 1979-1987. Shi,Y. (2002). Mechanisms of caspase activation and inh | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/39339 | - |
dc.description.abstract | 死亡相關蛋白激酶(Death associated protein kinase,DAPK)是一個由鈣�攜鈣素調控的絲胺酸�酪胺酸激酶,同時參與各式的細胞凋亡系統。在這份論文中,主要研究死亡相關蛋白激酶引起的細胞凋亡機制及其訊息傳遞,並且探討其功能上與某種磷酸化酪胺酸去磷酸酶(phosphotyrosine phosphatase)間的交互作用。在研究的第一部份,本論文顯示死亡相關蛋白激酶能藉著一個由內向外影響的機制(inside-out mechanism)來調降胞外基質受器(integrin)的活性,進一步抑制胞外基質受器所造成的細胞附著(cell adhesion)。死亡相關蛋白激酶經抑制細胞附著作用阻斷胞外基質受器所傳遞的存活訊息(survival signals)同時增加p53的活性,進而誘使細胞凋亡。為了証實這個觀點,本論文証明:無論是藉由胞外基質受器本身或是其下游的作用者FAK來增加胞外基質受器所傳邊的存活訊息路徑,均能中止死亡相關蛋白激酶誘發的細胞凋亡反應,同時死亡相關蛋白激酶也不能在無法進行失巢凋亡(anoikis resistant)的細胞中促使細胞凋亡現象的產生。因此,本論文探討死亡相關蛋白激酶的細胞凋亡機制,同時確認死亡相關蛋白激酶是失巢凋亡的誘發者。在研究的第二部份,試著找尋在死亡相關蛋白激酶的訊息傳導途徑中,能與死亡相關蛋白激酶相互作用分子。以死亡相關蛋白激酶的錨蛋白重覆區塊(ankyrin-repeat domain)為餌進行酵母菌雙雜交(yeast two-hybrid)系統分析,發現白血球共通抗原相關酪胺酸去磷酸酶(leukocyte common antigen related tyrosine phosphatase,LAR)能與死亡相關蛋白作用。本論文証明:死亡相關蛋白激酶能藉由錨蛋白重覆序列3到6的區域與LAR的去磷酸酶區間進行專一性的交互作用。更進一步發現死亡相關蛋白激酶對白血球共通抗原相關酪胺酸去磷酸酶的受質受限突變株(substrate-trapping mutant)具有較高的接合親合力,這意味著死亡相關蛋白激酶是白血球共通抗原相關酪胺酸去磷酸酶的受質。事實上,無論在試管內或活體中分析,死亡相關蛋白激酶均能有效地被白血球共通抗原相關酪胺酸去磷酸酶移除其酪胺酸491及492(Y491/492)上的磷酸根。除此之外,亦證明白血球共通抗原相關酪胺酸去磷酸酶能藉由這兩個胺基酸來增加死亡相關蛋白激酶的催化活性。因此,死亡相關蛋白激酶的各種生物活性,包括抑制細胞附著與誘發細胞凋亡,能在LAR過量表現下明顯增加。相形之下,利用RNA干擾技術(RNA interference)降低細胞內既有的白血球共通抗原相關酪胺酸去磷酸酶表現,會造成酪胺酸491�492磷酸化的增加及抑制死亡相關蛋白激酶的生物活性。這些結果顯示:經由酪胺酸491�492磷酸化,白血球共通抗原相關酪胺酸去磷酸酶是一個新發現的DAPK活化分子。因此,揭櫫於本論文中的死亡相關蛋白激酶-白血球共通抗原相關酪胺酸去磷酸酶相互作用及此激酶誘發細胞凋亡機制,均為死亡相關蛋白激酶的訊息傳導與其生物功能有了更進一步的認知與瞭解。 | zh_TW |
dc.description.abstract | Death associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase, and participates in various apoptotic systems. In this thesis, we studied the apoptotic mechanism of DAPK and its signaling and functional crosstalk with a phosphotyrosine phosphatase. In the first part of study, we demonstrated that DAPK suppresses integrin-mediated cell adhesion by down-regulating integrin activity through an inside-out mechanism. This adhesion-inhibitory effect of DAPK blocks integrin survival signals and up-regulates p53 protein, thereby inducing apoptosis. In support of this notion, we demonstrated that enforced activation of integrin survival pathways from either integrin itself or its downstream effector FAK abolishes the apoptotic effect of DAPK, and that DAPK can no longer induce apoptosis in the anoikis resistant cells. Thus, our study unravels that apoptotic mechanism of DAPK and identifies DAPK as an inducer of anoikis. In the second part of this thesis, we searched for DAPK interaction partners as part of our work to dissect DAPK signaling network. A yeast two-hybrid screen using the anykrin-repeat domain of DAPK as bait identified the leukocyte common antigen related tyrosine phosphatase (LAR) as a DAPK interacting protein. We showed that DAPK interacts specifically with LAR, through the ankyrin repeats 3-6 of DAPK and the phosphatase domain of LAR. The higher binding affinity of DAPK towards a substrate-trapping mutant of LAR suggests that DAPK functions as a substrate of LAR. Indeed, DAPK can be efficiently tyrosine-dephosphorylated by LAR both in vitro and in vivo, and this dephopshorylation event occurs at Y491/492 residues of DAPK. Furthermore, we demonstrated that LAR up-regulates the catalytic activity of DAPK through an Y491/492-dependent manner. As a consequence, the various biological activities of DAPK, such as anti-adhesion and apoptosis induction, are significantly promoted by overexpression of LAR. In contrast, knockdown of endogenous LAR by RNA interference technique results in an elevation of DAPK tyrosine phosphorylation at Y491/492 and inhibition of DAPK biological functions. These data indicate that LAR functions as a novel activator of DAPK through dephosphorylating DAPK at Y491/492. The uncovering of DAPK-LAR interplay and DAPK apoptotic mechanism in this thesis would shed light on the molecular mechanisms of DAPK signaling and biological functions. | en |
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dc.description.tableofcontents | TABLE CONTENTS..................................1
ABSTRACT........................................7 中文摘要..........................................8 ABBREVIATIONS.....................................9 1. APOPTOSIS........................................10 1.1 OVERVIEW.........................................10 1.2 CONNECTION OF CASPASE TO APOPTOSIS...............11 1.3 THE COMMON APOPTOTIC SIGNALING PATHWAYS............11 1.3.1 The mitochondrion-dependent cascade............11 1.3.2 The mitochondrion- independent cascade..........12 1.3.3 The crosstalk between these two cascades.........12 1.4 THE DEATH STAR: CONNECTION OF P53 TO APOPTOSIS.....13 1.4.1 Transcription-dependent pathways.................13 1.4.2 Transcription-independent pathways...............14 2.AUTOPHAGY............................................15 2.1 AUTOPHAGY IN CELL DEATH............................15 2.2 AUTOPHAGIC MECHANISM...............................16 3. DEATH ASSOCIATED PROTEIN KINASE(DAPK)...............17 3.1 DAPK FAMILY AND THE BASIC PROPERTIES...............17 3.2 DAPK IN CELL DEATH.................................18 3.3 THE TUMOR SUPPRESSION AND POSSIBLE NEURONAL FUNCTIONS OF DAPK.........20 4. INTEGRIN.............................................21 4.1 CELL ADHESION AND DE-ADHESION.......................21 4.2 INTEGRIN AND THE EXTRACELLULAR MATRIX...............22 4.3 FROM INTEGRIN STRUCTURE VIEW TO INTEGRIN ACTIVITY…....24 4.4 INTEGRIN SIGNALING NETWORK..........................24 4.4.1 Inside-out signaling..............................25 4.4.2 Outside-in signaling..............................26 4.4.2.1 Integrin signaling to actin cytoskeleton........26 4.4.2.2 Tyrosine phosphorylation-mediated signal transduction.........................................26 4.4.2.3 Activation of small G proteins.............27 4.4.2.4 Integrin and growth factor receptor cross-talk...28 5. ANOIKIS..............................................28 5.1 PHYSIOLOGICAL SIGNIFICANCE.......................28 5.2 ANOIKIS MECHANISM...................................29 5.2.1 Role of integrin in anoikis.....................29 5.2.2 Loss of FAK and PI3K/Akt signaling plays a key role in anoikis induction....................................30 5.2.3 Other molecules regulating anoikis work in coordination with integrins..........30 6. PROTEIN TYROSINE PHOSPHATASE (PTP)...................31 6.1 THE IMPORTANCE OF TYROSINE PHOSPHORYLATION........................................31 6.2 REGULATION BY KINASES AND PTPS.......................32 6.3 PTP STRUCTURE AND FUNCTION......................33 6.3.1 PTP classification............................33 6.3.2 Features of PTP active site....................34 CHAPTER I.......................35 DAP-KINASE INDUCES APOPTOSIS BY SUPPRESSING INTEGRIN ACTIVITY AND DISRUPTING MATRIX SURIVIAL SIGNALS.....................35 ABSTRACT.............................................35 INTRODUCTION.........................................36 RESULTS..............................................39 DAPK INDUCES APOPTOSIS-INDEPENDENT MORPHOLOGICAL CHANGES IN 293T CELLS...........................................39 DAPK SUPPRESSES INTEGRIN-MEDIATED CELL ADHESION AND SIGNAL TRANSDUCTION............................................40 DAPK SUPPRESSES INTEGRIN FUNCTION THROUGH AN INSIDE-OUT MECHANISM...............................................41 THE ANTI-ADHESION FUNCTION OF DAPK IS NOT DEPENDENT ON CELL TYPES..............................................42 DAPK PROMOTES APOPTOSIS BY BLOCKING ECM SURVIVAL SIGNALS...............................................42 DAPK INDUCES AN ANOIKIS-LIKE APOPTOSIS IN EPITHELIAL CELLS, WHICH IS REVERSED BY INTEGRIN ACTIVATION.........44 ACTIVATION OF INTEGRIN OR FAK BLOCKS DAPK-INDUCED UPREGULATION OF P53....................................46 DISCUSSION.............................................47 MATERIALS AND METHODS...............................................50 PLASMIDS..............................................50 CELL CULTURE, TRANSFORMATION AND RETROVIRAL INFECTION............................50 ANTIBODIES AND REAGENTS...............................50 ADHESION ASSAYS.................................................51 FLOW CYTOMETRY ANALYSIS..............................................51 IMMUNOPRECIPITATIONS..................................51 APOPTOSIS AND CASPASE ACTIVITY ASSAYS.................52 REPORTER ASSAYS.......................................52 SUPPLEMENTAL MATERIALS AVAILABLE......................52 CHAPTER II:...........................................53 ACTIVATION OF DAPK CATALYTIC ACTIVITY AND BIOLOGICAL FUNCTIONS BY LAR.......................................53 ABSTRACT...............................................53 INTRODUCTION...........................................54 DEATH-ASSOCIATED PROTEIN KINASE (DAPK) FAMILY..........54 IDENTIFICATION OF DAPK AND ITS DOMAIN PROPERTIES.............................................54 DAPK’S TARGETED SUBSTRATE AND CELLULAR FUNCTION..............................................55 PTP FAMILY............................................57 FEATURES OF THE PTP ACTIVATION........................58 THE RPTP-LAR..........................................58 LAR’S CELLULAR FUNCTIONS.............................59 SIGNIFICANCE..........................................61 MATERIALS AND METHODS.................................62 YEAST TWO-HYBRID SCREEN...............................62 CONSTRUCTS............................................62 CELL CULTURE AND TRANSFECTIONS........................62 ANTIBODIES............................................63 ADHESION ASSAYS:......................................63 IMMUNOPRECIPITATION:..................................63 IN VITRO DEPHOSPHORYLATION OF RECOMBINAT LAR-D1:......63 DAPK KINASE ASSAY:....................................64 APOPTOSIS ASSAYS.............................64 REDUCTION OF ENDOGENOUS LAR EXPRESSION USING SIRNA.................................64 RESULTS:............................................66 IDENTIFICATION OF LAR AS A DAPK-INTERACTING PROTEIN..................................66 MAPPING THE INTERACTING REGION OF LAR AND DAPK.........66 DAPK AND LAR INTERACT IN VIVO.........................67 LAR PROMOTES TYROSINE DEPHOSPHORYLATION OF DAPK....................................67 DAPK IS A DIRECT SUBSTRATE OF LAR..................68 MAPPING THE LAR-MEDIATED TYROSINE-DEPHOSPHORYLATION SITES ON DAPK............................................69 LAR PROMOTES DAPK CATALYTIC ACTIVITY THROUGH AN Y491/492-DEPENDENT MANNER....................................70 LAR PROMOTES THE ANTI-ADHESION EFFECT OF DAPK..........71 LAR PROMOTES DAPK-INDUCED ANOIKIS-TYPE CELL DEATH.......71 KNOCKDOWN OF ENDOGENOUS LAR ENHANCES DAPK TYROSINE PHOSPHORYLATION AND SUPPRESSES DAPK INDUCED ANTI-ADHESION FUNCTION.............................................72 DISCUSSION:..........................................73 TABLES..........................................77 TABLE 1. EXPRESSION OF HUST-21 EPITOPE ON 293T CELLS TRANSFECTED WITH VARIOUS CONSTRUCTS AND INCUBATED WITH OR WITHOUT MN2+.................77 TABLE 2: DAPK DELETION MUTANTS AND THEIR TYROSINE DEPHOSPHORYLATION STATE INFLUENCED BY LAR OVEREXPRESSION..................78 TABLE 3: SUMMARY OF THE EXTENT OF LAR-MEDIATED TYROSINE DEPHOSPHORYLATION OF DIFFERENT DAPK Y/F MUTANTS.......................................78 FIGURES:.......................................79 FIG. 1. DAPK INDUCES MORPHOLOGICAL CHANGES IN 293T CELLS.......................79 FIG. 2. DAPK INDUCES APOPTOSIS-INDEPENDENT MORPHOLOGICAL CHANGES IN 293T CELLS...................................80 FIG. 3. DAPK INHIBITS INTEGRIN-MEDIATED CELL ADHESION..................................81 FIG. 4. DAPK INHIBITS INTEGRIN-MEDIATED ECM SIGNAL TRANSDUCTION........................................82 FIG. 5. DAPK DOES NOT AFFECT CELL SURFACE EXPRESSION OF THE FIBRONECTIN AND LAMININ RECEPTORS..................83 FIG. 6. DAPK SUPPRESSES CELL ADHESION BY MODULATING INTEGRIN Β1 ACTIVITY.............................84 FIG. 7. DAPK SUPPRESSES INTEGRIN ACTIVITY............85 FIG. 8. DAPK INHIBITS ADHESION OF NIH3T3 CELLS BY INSIDE-OUT MODULATION OF INTEGRIN ACTIVITY...........86 FIG. 9. DAPK INDUCES APOPTOSIS IN CELLS PLATED ON MATRIX.............................87 FIG. 10. DAPK PROMOTES APOPTOSIS BY BLOCKING ECM SURVIVAL SIGNALS.88 FIG. 11. ACTIVATION OF INTEGRIN RESTORES FAK TYROSINE PHOSPHORYLATION.......................................89 FIG. 12. ACTIVATION OF INTEGRIN RESTORES FAK TYROSINE PHOSPHORYLATION AND PROTECTS CELLS FROM DAPK-INDUCED APOPTOSIS........................90 FIG. 13. DAPK INDUCES AN ANOIKIS-LIKE APOPTOSIS IN EPITHELIAL CELLS..................91 FIG. 14. DAPK CAN NO LONGER PROMOTE APOPTOSIS IN CELLS RESISTANT TO ANOIKIS....................92 FIG. 15. INTEGRIN OR FAK ACTIVATION BLOCKS THE INDUCTION OF P53 BY DAPK......................93 FIG. 16. A MODEL ILLUSTRATING THE MECHANISM BY WHICH DAPK INDUCES APOPTOSIS......................95 FIG. 17: IDENTIFICATION OF LAR AS DAPK-BINDING PROTEIN IN YEAST TWO-HYBRID SYSTEM..............................96 FIG. 18: GST-DAPK ANKYRIN REPEATS COULD PULL DOWN IN VITRO-TRANSLATED LAR PROTEIN.................................97 FIG. 19: ANKYRIN REPEATS 3-6 IS SUFFICIENT TO INTERACT WITH LAR (1680-1898).........................98 FIG. 20: NOT ONLY LAR D2 DOMAIN BUT ALSO LAR D1 DOMAIN CAN INTERACT WITH DAPK ANKYRIN REPEAT.......................99 FIG. 21: DAPK INTERACTS WITH LAR IN VIVO............100 FIG. 22: LAR INTERACTS WITH ENDOGENOUS DAPK.........101 FIG. 23: ENHANCEMENT OF DAPK BINDING AFFINITY BY LAR D/A MUTANT...102 FIG. 24: REDUCTION OF DAPK TYROSINE PHOSPHORYLATION IN RESPONSE TO OVER- EXPRESSION OF LAR.............103 FIG. 25: LAR OVEREXPRESSION DOES NOT AFFECT FAK TYROSINE PHOSPHORYLATION...................104 FIG. 26: OVEREXPRESSION OF LAR DOES NOT GENERALLY AFFECT TYROSINE PHOSPHORYLATION OF CELLULAR PROTEINS.......105 FIG. 27: SCHEMATIC REPRESENTATION OF THE DOMAIN STRUCTURE OF DIFFERENT DAPK DELETION MUTANTS.................106 FIG. 28: DELETION OF THE DEATH DOMAIN (DD) OF DAPK DOES NOT AFFECT LAR-INDUCED TYROSINE DEPHOSPHORYLATION OF DAPK.....................................107 FIG. 29: DAPK K-AR MUTANT CAN STILL BE DEPHOSPHORYLATED BY LAR OVEREXPRESSION................108 FIG. 30: DAPK K-CAM MUTANT IS INSENSITIVE TO LAR........................................109 FIG. 31: COMPARISON OF THE TYROSINE DEPHOSPHORYLATION STATES AMONG DIFFERENT DAPK Y/F MUTANTS IN RESPONSE TO LAR OVEREXPRESSION........110 FIG. 32: LAR DIRECTLY DEPHOSPHORYLATES DAPK IN VITRO.............................111 FIG. 33: ECTOPIC EXPRESSION OF LAR PROMOTES DAPK CATALYTIC ACTIVITY IN VIVO...................112 FIG. 34: LAR PROMOTES THE CATALYTIC ACTIVITY OF DAPK IN VIVO..............113 FIG. 35: OVEREXPRESSED LAR MODESTLY DECREASES THE ADHESION ABILITY OF 293T CELLS.................................114 FIG. 36: LAR PROMOTES DAPK-INDUCED CELL DETACHMENT............................115 FIG. 37: LAR PROMOTES DAPK-INDUCED APOPTOSIS..............................................116 FIG. 38: ESTABLISHMENT OF LAR SIRNA STABLE CLONES IN 293T CELLS…........117 FIG. 39: KNOCKDOWN OF LAR EXPRESSION ENHANCES THE TYROSINE PHOSPHORYLATION OF DAPK..................118 FIG. 40: KNOCKDOWN OF ENDOGENOUS LAR SUPPRESSES DAPK-MEDIATED CELL DETACHMENT.....................119 APPENDIX.............................................120 TABLE S1. PROTEIN IDENTIFIED TO INTERACT WITH DAPK ANKYRIN REPEAT IN THE YEAST TWO-HYBRID SCREEN..................120 FIG. S1: REDUCTION OF DAPK TYROSINE PHOSPHORYLATION IN RESPONSE TO OVER-EXPRESSION OF BOTH LARWT AND ITS PHOSPHATASE DOMAIN 2 DELETED MUTANT.................................................121 REFERENCES.............................................122 | |
dc.language.iso | zh-TW | |
dc.title | 探討DAPK引發細胞凋亡的機制及其受LAR之調控 | zh_TW |
dc.title | The Apoptotic Mechanism of Death-associated Protein Kinase and its Regulation by Protein Tyrosine Phosphatase LAR | en |
dc.type | Thesis | |
dc.date.schoolyear | 93-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 李芳仁,陳鴻震,施修明,孟子青 | |
dc.subject.keyword | 死亡相關蛋白激酶,細胞凋亡, | zh_TW |
dc.subject.keyword | integrin,DAPK,LAR,apoptosis, | en |
dc.relation.page | 139 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2005-01-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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