進階搜尋


 
系統識別號 U0026-0812200913361272
論文名稱(中文) 探討低硬度膠原蛋白誘發上皮細胞凋亡與自噬泡形成的機制
論文名稱(英文) Studies on low rigidity of collagen gel-induced apoptosis and autophagy in epithelial cells
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 95
學期 1
出版年 96
研究生(中文) 王耀賢
研究生(英文) Yao-Hsien Wang
電子信箱 pharwang@ms39.hinet.net
學號 s5888106
學位類別 博士
語文別 英文
論文頁數 114頁
口試委員 召集委員-謝達斌
口試委員-林銘德
口試委員-嚴仲陽
口試委員-呂增宏
指導教授-湯銘哲
中文關鍵字 自噬泡  低硬度基質  膠原蛋白  細胞凋亡 
英文關鍵字 collagen gel  apoptosis  autophagy  low substratum rigidity 
學科別分類
中文摘要 在本論文的第一部份的計畫中,我證實了第一型膠原蛋白凝膠而非第一型膠原蛋白凝膠鍍膜的培養盤會誘發細胞凋亡,特別是在上皮細胞。此現象指出低硬度基質會誘發細胞凋亡。使用年紀效應增加膠原蛋白纖維交聯程度或物理性破壞的方式來控制膠原蛋白的軟硬度。我發現膠原蛋白凝膠誘發細胞凋亡與基材軟硬度成反比。低硬度凝膠誘發之細胞凋亡無法被大量表現之Bcl-2蛋白所抑制,也沒有偵測出cytochrome c從粒線體被釋放。低硬度凝膠可誘發JNK的活化,但卻誘發c-Jun快速向下調節表現量且誘發c-Fos不正常表現。不論降低c-Jun的表現或將c-Fos在細胞內大量表現均可在不同上皮細胞誘發細胞死亡。抑制低硬度凝膠誘發之JNK活化同時可避免c-Fos的不正常表現,但只能部分減少膠原蛋白凝膠誘發細胞凋亡。總結以上,我們認為膠原蛋白凝膠誘發上皮細胞凋亡至少有一部分是經由AP-1蛋白質的去調節性所造成。
在本論文的第二部份的計畫中,將探討上皮細胞在膠原蛋白凝膠上誘發延遲性細胞凋亡的機制。低硬度膠原蛋白凝膠誘發上皮細胞凋亡雖發生於24小時之內,亦造成在一小時內細胞內鈣離子上升及內質網中鈣離子過度負載的現象,透過Annexin V的染色,此現象亦造成細胞外翻的現象。再則,低硬度的基材所造成AP-1蛋白家族的降解最終造成細胞凋亡現象則發生於24小時,所呈現的是DNA及細胞核的裂解現象。為了了解低硬度的基材所造成細胞外翻到細胞核裂解的過程中細胞生物學上所發生的現象,我檢視了細胞自噬泡的型成。我發現膠原蛋白凝膠在八小時內誘發正常上皮細胞中細胞自噬泡的生成但不發生於癌化細胞,乃是經由低硬度的基材所造成。抑制細胞自噬的生成反而加速細胞核的裂解但卻不影響早期的細胞膜翻轉現象。以細胞內鈣離子鰲合劑或鈣離子通道阻斷劑能防止低硬度的基材所誘發細胞自噬的生成。相對的,使用鈣離子的 ionophore則可誘發細胞自噬泡的生成,由此推測低硬度的基材誘發細胞內鈣離子上升而造成細胞自噬泡的生成。再則,低硬度的基材造成m-calpain的活化。然而活化的-calpain並不參與細胞自噬泡的生成及c-Jun的降解反應。總結以上,我們認為膠原蛋白凝膠誘發低硬度的基材誘發細胞內鈣離子上升而造成細胞自噬泡的生成,而細胞自噬泡可能參與延遲低硬度的基材造成c-Jun降解所造成細胞凋亡現象。
英文摘要 In this thesis, I established that collagen gel, but not collagen gel-coating, induced apoptosis exclusively in epithelial cell lines, which indicated that low substratum rigidity might trigger cell apoptosis. Alternation of collagen gel structure by age effect or sonication could decrease or elevate apoptosis ratio, respectively. I found that collagen-gel-induced apoptosis was inversely correlated with substratum rigidity. Low-substratum-rigidity collagen-gel-induced apoptosis was neither prevented by overexpression of Bcl-2 nor preceded by mitochondrial release of cytochrome c. Low substratum rigidity activated c-Jun N-terminal kinase (JNK), but it also rapidly downregulated c-Jun and triggered persistent aberrant expression of c-Fos. Either reduction of c-Jun expression or overexpression of c-Fos has been shown to induce apoptosis in several epithelial cells. Inhibition of low-substratum-rigidity-induced JNK activation prevented aberrant c-Fos expression, but only partially blocked low-substratum-rigidity-induced apoptosis. Taking these results together, I conclude that low-substratum-rigidity collagen gel induced apoptosis in epithelial cells, and that deregulation of AP-1 proteins mediated that apoptosis, at least in part.
The second project was to examine the mechanism whereby collagen gel induced a delay apoptosis in epithelial cells. Low rigidity of collagen gel induced apoptosis in epithelial cells within 24 h, whereas it induced an increase in intracellular Ca++ ([Ca++]i) and endoplasmic reticulum Ca++ overloading within 1 h, which lead to cell membrane flipping as assessed by positive Annexin V staining. In addition, low substratum rigidity triggered deregulation of AP-1 protein family, which eventually resulted in apoptosis within 24 h, as reflected by the presence of DNA and nuclear fragmentation. In order to understand the sequential biological events between membrane flipping and nuclear fragmentation as triggered by low substratum rigidity, I would like to know whether the formation of autophagy is involved in this process. I found that low substratum rigidity of collagen gel induced the formation of autophagy in normal epithelial but not transformed cells within 8 h. Inhibition of autophagy formation augmented nuclear fragmentation without alteration of membrane flipping at the early phase. Reduction of [Ca++]i by calcium chelators or channel blockers prevented low rigidity-induced formation of autophagy. In contrast, treatment of Ca++ ionophore induced formation of autophagy, suggesting that low substratum rigidity-induced intracellular Ca++ overload leads to the formation of autophagy. Moreover, low rigidity of collagen gel induced activation of m-calpain. However, activation of m-calpain was not involved in the formation of autophagy or degradation of c-Jun. Taken together, I conclude that low rigidity induces an increase in [Ca++]i and triggers formation of autophagy which contributes to delay low rigidity-induced apoptosis mediated by c-Jun degradation.
論文目次 Abstract---------------------------------------------------i
中文摘要 ------------------------------------------------iii
誌謝-------------------------------------------------------v
Chapter 1 Introduction
Most tissues are soft--------------------------------------1
Collagen gel and its physical property---------------------1
Detection of physical property of collagen gel-------------3
Soft substratum affects cell behaviors---------------------3
Type I programmed cell death: Apoptosis
Conventional pathway---------------------------------------4
Non-conventional pathway
JNK and AP-1 protein family--------------------------------6
Type II programmed cell death: Autophagy-------------------8
Signaling pathways of autophagy----------------------------9
Relationship between Type I and Type II programmed cell death----------10
Low rigidity triggers programmed cell death --------------11
Chapter 2 Materials and methods
Cell lines and cultures-----------------------------------13
Preparation of hydrated collagen gel----------------------13
Treatment with caspase inhibitors-------------------------14
DNA extraction and electrophoresis------------------------15
Hoechst 33258 staining and the assessment of nuclear area-15
Analysis of apoptosis ratio-------------------------------15
Immunoprecipitation and immunoblotting--------------------16
Scanning electron microscopy------------------------------16
Transmitted electron microscopy---------------------------17
Quantification of collagen gel rigidity-------------------17
Plasmid constructs and transfections----------------------18
Construction of a short hairpin RNA (shRNA) expression system---------------------18
Confocal microscopic images-------------------------------19
Statistics------------------------------------------------20
Chapter 3 Deregulation of AP-1 protein family in collagen gel-induced epithelial cell apoptosis mediated by low substratum rigidity.
Abstract--------------------------------------------------21
Introduction----------------------------------------------22
Results---------------------------------------------------25
Discussion------------------------------------------------34
Chapter 4 The role of autophagy formation in collagen gel-induced apoptosis mediated by low substratum rigidity
Abstract--------------------------------------------------40
Introduction----------------------------------------------42
Results---------------------------------------------------45
Discussion------------------------------------------------52
Chapter 5 Summary-----------------------------------------55
Reference-------------------------------------------------60
Figures---------------------------------------------------77
Resume of the author-------------------------------------113
參考文獻 Abate, C., Patel, L., Rauscher III, F.J. and Curran, T. (1990) Redox regulation of Fos and Jun DNA-binding activity in vitro. Science. 249,1157-1161.
Angel, P. and Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1072,129-57.
Arico, S., Petiot, A., Bauvy, C., Dubbelhuis, P.F., Meijer, A.J., Codogno, P. and Ogier-Denis, E. (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276, 35243-35246.
Ashkenazi, A. and Dixit, V.M. (1998) Death receptors: Signaling and modulation. Science. 281, 305-308.
Balaban, N. Q., Schwarz, U. S., Riveline, D., Goichberg, P., Tzur, G., Sabanay, I., Mahalu, D., Safran, S., Bershadsky, A., Addadi, L. and Geiger, B. (2001). Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat. Cell Biol. 3, 466-72.
Bames, H.A., Hutton, J.F. and Walters, K. (1989). An introduction to Rheology. Elsevier Science, Amsterdam, The Netherlands.
Barocas, V.H., Moon, A.G. and Tranquillo, R.T. (1995) The fibroblast-populated collagen microsphere assay of cell traction force--Part 2: Measurement of the cell traction parameter. J Biomech Eng. 11,164-170.
Behrens, A., Sibilia, M. and Wagner, E.F. (1999) Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cell proliferation. Nat Genet. 21,326-329.
Bernales, S., McDonald, K.L. and Walter, P. (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, 2311-2324.
Betsch, D.F. and Baer, E. (1980). Structure and mechanical properties of rat tai tendon. Biorheology. 17, 83-94.
Bernstein, L.R. and Liotta, L.A. (1994). Molecular mediators of interactions with extracellular matrix components in metastasis and angiogenesis. Curr. Opin. Oncl. 6, 106-113.
Bhoumik, A., Jones, N. and Ronai, Z. (2004) Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Proc Natl Acad Sci U S A. 101, 4222-4227.
Bossy-Wetzel, E., Bakiri, L. and Yaniv, M. (1997) Induction of apoptosis by the transcription factor c-Jun. EMBO J. 16,1695-709.
Boya, P., Gonzalez-Polo, R.A., Casares, N., Perfettini, J.L., Dessen, P., Larochette, N., Metivier, D., Meley, D., Souquere, S., Yoshimori, T., Pierron, G., Codogno, P. and Kroemer, G. (2005) Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025-1040.
Brummelkamp, T.R., Bernards, R. and Agami, R. (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science. 296,550-553.
Cain, K., Bratton, S.B., Langlais, C., Walker, G., Brown, D.G., Sun, X.M. and Cohen, G.M. (2000) Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes. J. Biol. Chem. 275, 6067-6070.
Chen, C.S., Mrksich, M., Huang, S., Whitesides, G.M. and Ingber, D.E. (1997). Geometric control of cell life and death. Science. 276, 1425-1428.
Chicurel, M.E., Chen, C.S. and Ingber, D.E. (1998). Cellular control lies in the balance of forces. Curr. Opin. Cell Biol. 10, 232-239.
Chinnaiyan, A.M., O’Rourke, K., Tewari, M. and Dixit, V.M. (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 81, 505-512.
Chiu, W.T., Wang, Y.H., Tang, M.J. and Shen, M.R. (2007) Soft substrate induces apoptosis by the disturbance of Ca2+ homeostasis in renal epithelial LLC-PK1 cells. J. Cell Physiol. (In press)
Choquet, D., Felsenfeld, D.P. and Sheetz, M.P. (1997). Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell. 88, 39-48.
Colotta, F., Polentarutti, N., Sironi, M. and Mantovani, A. (1992) Expression and involvement of c-fos and c-jun proto-oncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J. Biol. Chem. 267,18278-18283.
Curran, T. and Franza, Jr., B.R. (1988) Fos and Jun: the Ap-1 connection. Cell. 55,395-397.
Demarchi, F., Bertoli, C., Copetti, T., Tanida, I., Brancolini, C., Eskelinen, E.L. and Schneider, C. (2006) Calpain is required for macroautophagy in mammalian cells. J. Cell Biol. 175, 595-605.
Denecker, G., Vercammen, D., Steemans, M., Vanden Berghe, T., Brouckaert, G., Van Loo ,G., Zhivotovsky, B., Fiers, W., Grooten, J., Declercq, W. and Vandenabeele, P. (2001) Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria. Cell Death Differ. 8, 829-840.
Distel, R.J., Ro, H.S., Rosen, B.S., Groves, D.L. and Spiegelman, B.M. (1987) Nucleoprotein complexes that regulate gene expression in adipocyte differention: direct participation of c-fos. Cell. 49,835-844.
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.
Dubbelhuis, P.F., Van Sluijters, D.A., Blommaart, E.F.C., Gustafson, L.A., Van Woerkom, G.M., Herling, A.W., Burger, H.J. and Meijer, A.J. (2002) Inhibition of autophagy proteolysis by inhibition of phosphoinositide 3-kinase can interfere with the regulation of glycogen synthesis in isolated hepatocytes. Biochem. J. 368, 827-833.
Eastman, A. (1995). Assays for DNA fragmentation, endonucleases, and intracellular pH and Ca2+ associated with apoptosis. Methods Cell Biol. 46, 41-55.
Eferl, R., Sibilia, M., Hilberg, F., Fuchsbichler, A., Kufferath, I., Guertl, B., Zenz, R., Wangner, E.F. and Zatloukal, K. (1999) Functions of c-Jun in liver and heart development. J Cell Biol. 145,1049-1061.
Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A. and Nagata, S. (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 391, 43-50.
Engler, A.J., Griffin, M.A., Sen, S., Bonnemann, C.G., Sweeney, H.L. and Discher, D.E. (2004) Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenviroments. J. Cell Biol. 166, 877-887.
Ferri, K.F. and Kroemer, G. (2001) Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 3, E255-263.
Flanagan, L.A., Ju, Y.E., Marg, B., Osterfield, M. and Janmey, P.A. (2002) Neurite branching on deformable substrates. Neuroreport. 13, 2411-2415.
Frisch, S.M., and Francis, H. (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619-626.
Galbraith, C.G., Yamada, K.M. and Sheetz, M.P. (2002). The relationship between force and focal complex development. J. Cell Biol. 159, 695-705.
Gao, M., Labuda, T., Xia, Y., Gallagher, E., Fang, D., Liu, Y.C. and Karin, M. (2004) Jun turnover is control through JNK-dependent phosphorylation of the E3 ligase Itch. Science. 306, 271-275.
Garcia, A.J. and Reyes, C.D. (2005) Bio-adhesive surfaces to promote osteoblast differentiation and bone formation. J. Dent. Res. 84, 407-413.
Giraud-Guille, M.M. (1989). Liquid crystalline phases of sonicated type I collagen. Biol Cell. 67, 97-101.
Gonzalez-Polo, R.A., Boya, P., Pauleau, A.L., Jalil, A., Larochette, N., Souquere, S., Eskelinen, E.L., Pierron, G., Saftig, P. and Kroemer, G. (2005) The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. J. Cell Sci. 118, 3091-3102.
Gordon, P.B., Holen, I., Fosse, M., Rotnes, J.S. and Segien, P.O. (1993) Dependence of Hepatocytic autophagy on intracellularly sequestered calcium. J. Biol. Chem. 268, 26107-26112.
Hahn, W.C., Counter, C.M., Lundberg, A.S., Beijersbergen, R.L., Brooks, M.W., and Weinberg, R.A. (1999). Creation of human tumour cells with defined genetic elements. Nature. 400, 464-468.
Harding, T.M., Morano, K.A., Scott, S.V. and Klionsky, D.J. (1995) Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602.
Haut, T. and Haut, R. (1997). The state of tissue hydration determines strain-rate-sensitive stiffness of human patellar tendon. J. Biomech. 30, 79-81.
Hetz, C., Bernasconi, P., Fisher, J., Lee, A., Bassik, M.C., Antonsson, B., Brandt, G.S., Iwakoshi, N.N., Schinzel, A., Glimcher, L.H. and Korsmeyer, S.J. (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1a. Science. 312, 572-576.
Hey, K.B., Lachs, C.M., Raxworthy, M.J. and Wood, E.J. (1990) Crosslinked fibrous collagen for use as a dermal implant: Control of the cytotoxic effects of glutaraldehyde and dimethylsuberimidate. Biotechnol. Appl. Biochem. 12, 85-93.
Hirai, S., Ryseck, R., Mechta, F., Bravo, R. and Yaniv, M. (1989) Characterization of jun D: a new member of the jun proto-oncogene family. EMBO J. 8, 1433-1439.
Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.L., Schneider, P., Seed, B. and Tschopp, J. (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489-495.
Ho, S.P., Sulyanto, R.M., Marshall, S.J. and Marshall, G.W. (2005) The cementum-dentin junction also contains glycosaminoglycans and collagen fibrils. J. Struct. Biol. 151, 69-78.
Hsu, H., Xiong, J. and Goeddel, D.V. (1995) The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 81, 495-504.
Hsu, S., Jamieson, A.M. and Blackwell, J. (1994). Viscoelastic studies of extracellular matrix interactions in a model native collagen gel system. Biorheology. 31, 21-36.
Hu, Y.J. (2006) Low substratum rigidity induces ubiquitin ligase CUL1 mediated-c-Jun degradation in nucleus of epithelial cells. (Master thesis)
Huang, L.L., Sung, H.W., Tsai, C.C. and Huang, D.M. (1998) Biocompatibility study of a biological tissue fixed with a naturally occurring crosslinking reagent. J. Biomed. Mater. Res. 42, 568-576.
Ichimura, Y., Kirisako, T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. (2000) A ubiquitin-like system mediates protein lipidation. Nature. 408, 488-492.
Ingber, D.E. (1993). Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J. Cell Sci. 104, 613-27.
Jia, L., Dourmashkin, R.R., Allen, P.D., Gray, A.B., Newland, A.C. and Kelsey, S.M. (1997) Inhibition of autophagy abrogates tumor necrosis factor alpha induced apoptosis in human T-lymphoblastic leukaemic cells. Br. J. Haematol. 98, 673-685.
Jiang, G., Giannone, G., Critchley, D.R., Fukumoto, E. and Sheetz, M.P. (2003). Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature. 424, 334-7.
Jiang, S.T., Chiang, H.C., Yang, T.P., Chuang, W.J. and Tang, M.J. (1999). The role of fibronectin deposition in cystogenesis of MDCK cells. Kidney Int. 56, 92-103.
Jiang, S.T., Chuang, W.J. and Tang, M.J. (2000b). The role of fibronectin deposition in branching morphogenesis of MDCK cells. Kidney Int. 57, 1860-1867.
Jiang, S.T., Yang, T.P., Huang, J.J., Hsu, C.C. and Tang, M.J. (2000a). The age effects of type I collagen on morphogenesis of MDCK cells. Kidney Int. 57, 1539-1548.
Jiang, X. and Wang, X. (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J. Biol. Chem. 275, 31199-311203.
Juliano, R.L. and Haskill, S.J. (1993). Signal transduction from the extracellular matrix. J Cell Biol. 120, 577-585.
Jurgensmeier, J.M., Xie, Z., Deveraux, Q., Ellerby, L., Bredesen, D. and Reed, J.C. (1998) Bax directly induces release of chtochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA. 95, 4997-5002.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y. and Yoshimori, T. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728.
Kagan H.M. (2000) Intra- and extracellular enzyme of collagen biosynthesis as biological and chemical targets in the control of fibrosis. Acta. Trop. 77, 147-152.
Kawahara, A., Ohsawa, Y., Matsumura, H., Uchiyama, Y. and Nagata S. (1998) Caspase-independent cell killing by Fas-associated protein with death domain. J. Cell Biol. 143, 1353-1360.
Kihara, A., Kabeya, Y., Ohsumi, Y. and Yoshimori, T. (2001) Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep. 2, 330-335.
Kirisako, T., Baba, M., Ishihara, N., Miyazawa, K., Ohsumi, M., Yoshimori, T., Noda, T., and Ohsumi,Y. (1999) Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J. Cell Biol. 147, 435-446.
Klionsky, D.J., and Emr, S.D. (2000) Autophagy as a regulated pathway of cellular degradation. Science. 290, 1717-1721.
Klionsky, D.J. (2005) The molecular machinery of autophagy: unanswered questions. J. Cell Sci. 118, 7-18.
Kluck, R.M., Bossy-Wetzel, E., Green, D.R. and Newmeyer, D.D. (1997) The release of Cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 275, 1132-1136.
Kong, H.J., Polte, T.R., Alsberg, E. and Mooney, D.J. (2005) FRET measurements of cell-traction forces and nano-scale clustering of adhesion ligands varied by substrate stiffness. Proc. Natl. Acad. Sci. USA. 102, 4300-4305.
Lardeux, B.R. and Mortimore, G.E. (1987) Amino acid and hormonal control of macromolecular turnover in perfused rat liver. Evidence for selective autophagy. J. Biol. Chem. 262, 14514-14519.
Lee, M.S., Yang, J.H., Salehi, Z., Arnstein, P., Chen, L.S., Jay, G.. and Rhim, J.S. (1993) Neoplastic transformation of a human keratinocyte cell line by the v-fos oncogene. Oncogene. 8,387-393.
Le-Niculescu, H., Bonfoco, E., Kasuya, Y., Claret, F.X., Green, D.R. and Karin, M. (1999) Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. Mol Cell Biol. 19, 751-63.
Levine, B. and Klionsky, D.J. (2004) Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell. 6, 463-477.
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.
Liang, X.H., Jackson, S., Seaman, M., Brown, K., Kempkes, B. and Hibshoosh, H. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 402, 672-676.
Lin, H.H., Yang, T.P., Jiang, S.T., Yang, H.Y. and Tang, M.J. (1999). Bcl-2 overexpression prevents apoptosis-induced Madin-Darby canine kidney simple epithelial cyst formation. Kidney Int. 55, 168-178.
Lindmo, K. and Stenmark, H. (2005) Regulation of membrane traffic by phosphoinosited 3-kinases. J. Cell Sci. 119, 605-614.
Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951). Protein measurement for Folin phenol reagent. J. Biol. Chem. 251, 165-175.
Lum, J.J., Bauer, D.E., Kong, M., Harris, M.H., Li, C., Lindsten, T. and Thompson, C.B. (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 120, 237-248.
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.
McAteer, J.A. and Cavanagh, T.J. (1982). Medium hydrated collagen gel as an explant support in organ culture. J. Tissue Cult. Methods. 7, 117-122.
MacKintosh, F.C., Kas, J, and Janmey, P.A. (1995) Elasticity of semiflexible biopolymer networks. Phys Rev Lett. 75, 4425–4428.
MacLaren, A., Black, E.J., Clark, W. and Gillespie, D.A.F. (2004) c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation. Mol. Cell. Biol. 24, 9006-9018.
Miller, A.D., Curran, T. and Verma, I.M. (1984) C-fos protein can induce cellular transformation: a novel mechanism of activation of cellular oncogene. Cell. 36, 51-60.
Mizushima, N., Noda, T. and Ohsumi, Y. (1999) Apg16 is required for the function of Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J. 18, 3888-3896.
Mochitate, K., Pawelek, P. and Grinnell, F. (1991). Stress relaxation of contracted collagen gels: Disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. Exp. Cell Res. 193, 198-207.
Mooney, D.J., Langer, R. and Ingber, D.E. (1995). Cytoskeleton filament assembly and control of cell spreading and function by extracellular matrix. J. Cell Sci. 108, 2311-2320.
Mortimore, G.E. and Schworer, C.M. (1977) Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature. 270, 174-176.
Nakagawa, T. and Yuan, J. (2000) Cross-talk between cysteine protease families: activation of caspase 12 by calpain in apoptosis. J. Cell Biol. 150, 887-894.
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A. and Yuan, J. (2000) Caspase 12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-b. Nature. 403, 98-103.
Nateri, A.S., Riera-Sens, L., Costa, C.D. and Behrens, A. (2004) The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science. 303, 1374-1378.
Nishi, C., Nakajima, N. and Ikada, Y. (1995) In vitro evaluation of cytotoxicity of diepoxy compounds used for biomaterial modification. J. Biomed. Mater. Res. 29, 829-834.
Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tamii, I., Yoshinaga, K., Shiosaka, S., Hammarback, J.A., Urano, F. and Imaizumi, K. (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220-9231.
Ohsumi, Y. (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat. Rev. Mol. Cell Biol. 2, 211-216.
Paszek, M.J., Zahir, N., Johnson, K.R., Lakins, J.N., Rozenberg, G.I., Gefen,A., Reinhart-King, C.A., Margulies, S.S., Dembo, M., Boettiger, D., Hammer, D.A. and Weaver, V.M. (2005) Tensional homeostasis and the malignant phenotype. Cancer cell. 8, 241-254.
Pelham, R. J. Jr., and Wang, Y.L. (1997). Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl. Acad. Sci. USA. 94, 13661-13665.
Petiot, A., Ogier-Denis, E., Blommaart, E.F., Meijer, A.J. and Codogno, P. (2000) Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 275, 992-998.
Pokharna, H.K., Monnier, V., Boja, B. and Moskowitz, R.W. (1995) Lysyl oxidase and maillard reaction-mediated crosslinks in aging and osteoarthritic rabbit cartilage. J. Orthop. Res. 13, 13-21.
Re, F., Zanetti, A., Sironi, M., Polentautti, 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.
Reginato, M.J., Mills, K.R., Paulus, J.K., Lynch, D.K., Sgroi, D.C., Debnath, J., Muthuswamy, S.K. and Brugge, J.S. (2003) Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat. Cell Biol. 5, 733-740.
Rich, K.A., Zhan, Y. and Blanks, J.C. (1997) Aberrant expression of c-fos accompanies photoreceptor cell death in the rd mouse. J. Neurobiol. 32, 593-612.
Ruoslahti, E. and Reed, J.C. (1994) Anchorage dependence, integrins, and apoptosis. Cell. 77, 477-478.
Ruther, U., Wagner, E.F. and Muller, R. (1985) Analysis of the differentiation-promoting potential of inducible c-fos genes introduced into embryonal cells. EMBO J. 4,1775-1781.
Ryder, K. and Nathans, D. (1988) Induction of proto-oncogene c-jun by serum growth factors. Proc Natl Acad Sci USA. 85,8464-8467.
Ryder, K., Lanahan, A., Perez-Albuerne, E. and Nathans, D. (1989) Jun-D: a third member of the Jun gene family. Proc Natl Acad Sci USA. 86,1500-1503.
Re, F., Zanetti, A., Sironi, M., Polentautti, 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.
Redden, R.A. and Doolin, E.J. (2003) Collagen crosslinking and cell density have distinct effect on fibroblast-mediated contraction of collagen gels. Skin Res. Tech. 9,290-293.
Ruoslahti, E. and Reed, J.C. (1994). Anchorage dependence, integrins, and apoptosis. Cell. 77, 477-478.
Sakahira, H., Enari, M. and Nagata, S. (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature. 391, 96-99.
Sakai, T., Larsen, M. and Yamada. K.M. (2003). Fibronectin requirement in branching morphogenesis. Nature. 423, 876-81.
Schaller, M.D., Borgman, C.A., Cobb, B.S., Vines, R.R., Reynolds, A.B. and Parsons, J.H. (1992) pp125FAK, a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl. Acad. Sci. USA. 89, 5192-5196.
Schwartz, A.L., Brandt, R.A., Geuze, H. and Ciechanover, A. (1992) Stress-induced alterations in autophagic pathway: relationship to ubiquitin system. Am. J. Physiol. 262, C1031-C1038.
Shanmugathasan, M. and Jothy, S. (2000). Apoptosis, anoikis and their relevance to the pathobiology of colon cancer. Pathol. Int. 50, 273-279.
Sheetz, M.P., Felsenfeld, D.P. and Galbraith, C.G. (1998). Cell migration: regulation of force on extracellular-matrix-integrin complexes. Trends Cell Biol. 8, 51-54.
Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C.B. and Tsujimoto, Y. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 6, 1221-1228.
Shimizu, S., Narita M. and Tsujimoto, Y. (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 399, 483-487.
Smeyne, R.J., Vendrell, M., Hayward, M., Baker, S.J., Miao, G..G.., Schilling, K., Robertson, L.M., Curran, T. and Morgan, J.I. (1993) Continuous c-fos expression precedes programmed cell death in vivo. Nature. 363, 166-169.
Speer, D.P., Chvapil, M., Eskelson, C.D. and Ulreich, J. (1980) Biological effectsof residual glutaraldehyde in glutaraldehyde-tanned collagen biomaterials. J. Biomed. Mater. Res. 14, 753-764.
Srinivasula, S.M., Datta, P., Fan, X.J., Fernandes-Alnemri, T., Huang, Z. and Alnemri, E.S. (2000) Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J. Biol. Chem. 275, 36152-36157.
Stading, M. and Langer, R. (1999). Mechanical shear properties of cell polymer cartilage constructs. Tissue Eng. 5, 241-250.
Storm, C., Pastore, J.J., MacKintosh, F.C., Lubensky, T.C. and Janmey. P.A. (2005) Nonlinear elasticity in biological gels. Nature. 435, 191-194.
Suzuki, K., Kirisako, T., Kamada, Y., Mizushima, N., Noda, T. and Ohsumi, Y. (2001) The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20, 5971-5981.
Takeuchi, H., Kondo, Y., Fujiwara, K., Kanzawa, T., Aoki, H., Mills, G.B. and Kondo, S. (2005) Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 65, 3336-3346.
Tanida, I., Mizushima. N., Kiyooka, M., Ohsumi, M., Ueno, T., Ohsumi, Y. and Kominami. E. (1999) Apg7p/Cvt2p: A novel protein-activating enzyme essential for autophagy. Mol. Biol. Cell. 10, 1367-1379.
Tan, J.L., Tien, J., Pirone, D.M., Gray, D.S., Bhadriraju, K. and Chen, C.S. (2003). Cell lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl. Acad. Sci. USA. 100, 1484-1489.
Tang, M.J., Hu, J.J., Lin, H.H., Chiu, W.T. and Jiang, S.T. (1998). Collagen gel overlay induces apoptosis of polarized cells in cultures: disoriented cell death. Am. J. Physiol. 275 (Cell Physiology. 44), C921-C931.
Tassa, A., Roux, M.P., Attaix, D. and Bechet D.M. (2003) Class III phosphoinositide 3-kinase-beclin 1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem. J. 376, 577-586.
Thumm, M., Egner, R. Koch, B., Schlumpberger, M., Straub, M., Veenhuis, M. and Wolf, D. H. (1994) Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 349, 275–280.
van Luyn, M.J., van Wachem, P.B., Damink, L.O., Dijkstra, P.J., Feijen, J. and Nieuwenhuis, P. (1992) Relations between in vitro cytotoxicity and crosslinked dermal sheep collagens. J. Biomed. Mater. Res. 26, 1091-1110.
Wang, H.B., Dembo, M. and Wang, Y.L. (2000). Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell Physiol. 279, C1345-C1350.
Wang, Y.H., Chiu, W.T., Wang, Y.K., Wu, C.C., Chen, T.L., Teng, C.F., Chang, W.T., Chang, H.C. and Tang, M.J. (2007) Deregulation of AP-1 protein family in collagen gel-induced epithelial cell apoptosis mediated by low substratum rigidity. J. Biol. Chem. 282, 752-763.
Wang, Y.K., Lin, H.H. and Tang, M.J. (2001). Collagen gel overlay induces two phases of apoptosis in MDCK cells. Am. J. Physiol. Cell Physiol. 280, C1440-C1448.
Wang, Y.K., Wang, Y.H., Wang, C.Z., Sung, J.M., Chiu, W.T., Lin, S.H., Chang, Y.H. and Tang, M.J. (2003). Rigidity of collagen fibrils controls collagen gel-induced down-regulation of focal adhesion complex proteins mediated by a2b1 integrin. J. Bio. Chem. 278, 21886-21892.
Ware, C.F., VanArsdale, S. and VanArsdale, T.L. (1996) Apoptosis mediated by the TNF-related cytokine and receptor families. J. Cell Biochem. 60, 47-55.
Watson, A., Eilers, A., Lallemand, D., Kyriakis, J., Rubin, L.L. and Ham, J. (1998) Phosphorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons. J. Neurosci. 18, 751-762.
Wenzel, A., Grimm, C., Marti, A., Kueng-Hitz, N., Hafezi, F., Niemeyer, G. and Reme, C.E. (2000) c-Fos controls the “Private Pathway” of light-induced apoptosis of retinal photoreceptors. J. Neurosci. 20,81-88.
Whitmarsh, A.J. and Davis, R.J. (1996) Transcription factor AP-1 regulated by mitogen-activated protein kinase signal transduction pathways. J. Mol. Med. 74,589-607.
Wisdom, R., Johnson, R.S. and Moore, C. (1999) C-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J. 18, 188-197,
Wu, C.C., Ding, S.J., Wang, Y.H., Tang, M.J. and Chang, H.C. (2005) Mechanical properties of collagen gel derived from rats of different ages. J Biomater Sci. Polymer Edn. 16,1261-1275.
Woo, M., Hakem, A., Elia, A.J., Hakem, R., Duncan, G.S., Patterson, B.J. and Mak T.W. (1999) In vivo evidence that caspase-3 is required for Fas-mediated apoptosis of hepatocytes. J. Immunol. 163, 4929-16.
Yang, J., Liu, X., Bhalla, K., Kim, C.N., Ibrado, A.M., Cai, J., Peng, T., Jones, D.P. and Wang, X.D. (1997). Prevention of apoptosis by Bcl-2: release of cytochrome C from mitochondria blocked. Science. 275, 1129-1132.
Yawata A., Adachi, M., Okuda, H., Naishiro, Y., Takamura, T., Hareyama, M., Takayama, S., Reed, J.C. and Imai, K. (1999). Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene. 16, 2681-2686.
Yoneda, T., Imaizumi, K., Oono, K., Yui, d., Gomi, F., Katayama, T. and Tohyama, M. (2001) Activation of caspase 12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to ER stress. J. Biol. Chem. 276, 13935-13940.
Yorimitsu, T., Nair, U., Yang, Z. and Klionsky, D.J. (2006) Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281, 30299-30304.
Yousefi, S., Perozzo, R., Schmid, I., Ziemiechi, A., Schaffner, T., Scapozza, L., Brunner, T. and Simon, H.U. (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 10, 1124-1132.
Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E.H. and Lenardo, M.J. (2003) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 304, 1500-1502.
Zeng, X., Overmeyer, J.H. and Maltese, W.A. (2006) Functional specificity of the mammalian Beclin-Vps34 PI3-Kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci. 119, 259-270.
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2007-02-12起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2007-02-12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