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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳益群(Yi-Chun Wu) | |
| dc.contributor.author | Chun-Yi Huang | en |
| dc.contributor.author | 黃春怡 | zh_TW |
| dc.date.accessioned | 2021-06-16T17:15:20Z | - |
| dc.date.available | 2017-08-27 | |
| dc.date.copyright | 2012-08-27 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-20 | |
| dc.identifier.citation | Avery, L., Horvitz, H.R., 1987. A cell that dies during wild-type C. elegans development can function as a neuron in a ced-3 mutant. Cell 51, 1071-1078.
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Wu, Y.C., Stanfield, G.M., Horvitz, H.R., 2000. NUC-1, a caenorhabditis elegans DNase II homolog, functions in an intermediate step of DNA degradation during apoptosis. Genes Dev 14, 536-548. Yan, N., Chai, J., Lee, E.S., Gu, L., Liu, Q., He, J., Wu, J.W., Kokel, D., Li, H., Hao, Q., Xue, D., Shi, Y., 2005. Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437, 831-837. Yang, M., Sun, J., Sun, X., Shen, Q., Gao, Z., Yang, C., 2009. Caenorhabditis elegans protein arginine methyltransferase PRMT-5 negatively regulates DNA damage-induced apoptosis. PLoS Genet 5, e1000514. Yang, X., Chang, H.Y., Baltimore, D., 1998. Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Science 281, 1355-1357. Yu, X., Lu, N., Zhou, Z., 2008. Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells. PLoS Biol 6, e61. Yu, X., Odera, S., Chuang, C.H., Lu, N., Zhou, Z., 2006. C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells. Dev Cell 10, 743-757. Yuan, J., Shaham, S., Ledoux, S., Ellis, H.M., Horvitz, H.R., 1993. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75, 641-652. Zou, H., Henzel, W.J., Liu, X., Lutschg, A., Wang, X., 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90, 405-413. Zou, W., Lu, Q., Zhao, D., Li, W., Mapes, J., Xie, Y., Wang, X., 2009. Caenorhabditis elegans myotubularin MTM-1 negatively regulates the engulfment of apoptotic cells. PLoS Genet 5, e1000679. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63632 | - |
| dc.description.abstract | 在多細胞生物中，計畫性細胞死亡(細胞凋亡)是由基因嚴密調控的路徑，不正常的活化細胞死亡會造成退化性的病徵，然而不當的抑制細胞死亡也會造成腫瘤的生成。在哺乳動物細胞中，廣泛被研究調控細胞凋亡的分子機制主要可以分成內部和外部二個路徑。內部(粒線體)的路徑是藉由內在刺激傳遞至粒線體所引發，而外部(死亡接受器)的路徑則是由死亡的配合基與帶有死亡區域的接受器與轉接器相互作用而活化。就目前為止，還未有外部死亡路徑的調控在線蟲中被報導。根據我們的研究，我們找到一個已知參與在細胞遷移功能且具有死亡區域蛋白的膜接受器─UNC-5。在線蟲之前的研究中，UNC-5/Unc5和他共同的接受器UNC-40/DCC以及其配合基UNC-6(netrin)、UNC-129 (TGF-β)對於指導周圍細胞和生長錐向外移動都是必要的。在我們的研究中發現，當UNC-5失去功能時會造成死細胞數目減少，亦會使活細胞多存活過來。反之，過量表現UNC-5 則會造成大量的細胞死亡，推論UNC-5 可以正向調控細胞死亡。此外，我們也發現UNC-129 (TGF-β)這個分泌型的配合基可以與UNC-5 作用，共同來調控細胞死亡。這也是第一個證據顯示細胞死亡可以透過外來的訊號UNC-129 活化和啟動。進一步的生化與遺傳分析顯示我們另找到一個位於UNC-5下游且直接與UNC-5 作用的蛋白質激酶─SRC-2。我們推論當UNC-5 接受到外來UNC-129 的訊號時，即可將死亡訊息藉由與SRC-2的直接作用而將訊號傳遞下去以啟動促進細胞死亡。執行計畫性細胞死亡最重要的步驟就是活化凋亡蛋白酶(caspases)。在線蟲(C.elegans)中，已知EGL-1(BH3 only)，CED-9 (Bcl-2)，CED-4 (Apaf-1) 和CED-3 caspase 組成了細胞死亡的核心路徑。在此我們另外找到了一個位於CED-3 caspase上游的新細胞死亡調控基因─eif-3.K。當eif-3.K(lf)皆會造成生殖與體細胞屍體數目減少，反之eif-3.K(gf)則能使更多的細胞死亡。利用特定表現的promoter，發現eif-3.K將以細胞自主性(cell-autonomous)的方式來促進細胞死亡。此外，當eif-3.K(lf)可顯著的抑制ced-4大量表現所造成的細胞死亡，卻無法抑制ced-3所造成的細胞死亡，此結果顯示細胞死亡過程中，對於eif-3.K 是有不同的需求。反之，當ced-3(lf) 卻可抑制eif-3.K表現所造成的細胞死亡，這說明eif-3.K 促進細胞死亡時是需要ced-3 且位於ced-3上游來啟動這過程。EIF-3.K 是一個從胚胎到成蟲都可表現在細胞質的高度保留性蛋白，以結構功能上分析顯示，EIF-3.K中具有61個a.a 的WH domain，不但可以參與 protein-DNA/RNA 間的互相作用，對於EIF-3.K 促進細胞死亡的能力上也是必須且必要的。由於人類的eIF3k 亦可部分取代線蟲中eif-3.K 促進細胞死亡的能力，表示由WH domain 所決定之EIF-3.K調控細胞死亡的過程是在不同物種間皆具有高度保守性。 | zh_TW |
| dc.description.abstract | Programmed cell death (apoptosis) is an important developmental process that removes unnecessary or harmful cells and maintains tissue homeostasis, size and shape. Apoptosis in mammals is induced by either intrinsic death stimuli or extrinsic cue through proapoptotic receptors. In C. elegans, however, apoptosis is long thought to be regulated in a cell-autonomous fashion and no external death signal or pro-apoptotic receptor has been identified. We have characterized one death-domain (DD)-containing protein UNC-5, a previously identified guidance receptor mediating axon replusion and cell migration away from extracellular cues UNC-6/netrin and attraction towards UNC-129/TGF-β. Loss-of-function mutations in unc-5 result in a decrease of cell corpses and extra surviving cells, whereas over-expression of unc-5 significantly increases cell corpses. unc-5 likely acts in a cell-autonomous manner to promote apoptosis. In addition, we find that UNC-129, a secreted-form ligand, acts with UNC-5 to promote apoptosis and needs to be secreted for the function. This is the first evidence showing that programmed cell death can be regulated by the external signal UNC-129/TGF-β. Further genetic and biochemical analyses reveal that SRC-2, a nonreceptor tyrosine kinase, interacts with the UNC-5 intracellular region in vitro and acts downstream of unc-5 to mediate apoptosis. We propose that in response to UNC-129, UNC-5 receptor transduces the death signal by interacting with SRC-2 to promote apoptosis. In C. elegans, the core cell death regulators EGL-1(a BH3 domain-containing protein), CED-9 (Bcl-2), and CED-4 (Apaf-1) act in an inhibitory cascade to activate the CED-3 caspase. Here we have identified an additional component eif-3.K (eukaryotic translation initiation factor 3 subunit k) that acts upstream of ced-3 to promote programmed cell death. The loss of eif-3.K reduced cell deaths in both somatic and germ cells, whereas the overexpression of eif-3.K resulted in a slight but significant increase in cell death. Using a cell-specific promoter, we show that eif-3.K promotes cell death in a cell-autonomous manner. In addition, the loss of eif-3.K significantly suppressed cell death-induced through the overexpression of ced-4, but not ced-3, indicating a distinct requirement for eif-3.K in apoptosis. Reciprocally, a loss of ced-3 suppressed cell death induced by the overexpression of eif-3.K. These results indicate that eif-3.K requires ced-3 to promote programmed cell death and that eif-3.K acts upstream of ced-3 to promote this process. The EIF-3.K protein is ubiquitously expressed in embryos and larvae and localizes to the cytoplasm. A structure-function analysis revealed that the 61 amino acid long WH domain of EIF-3.K, potentially involved in protein-DNA/RNA interactions, is both necessary and sufficient for the cell death-promoting activity of EIF-3.K. Because human eIF3k was able to partially substitute for C. elegans eif-3.K in the promotion of cell death, this WH domain-dependent EIF-3.K-mediated cell death process has potentially been conserved throughout evolution. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T17:15:20Z (GMT). No. of bitstreams: 1 ntu-101-F92b43013-1.pdf: 4541395 bytes, checksum: 2664de3376532591eb11799ec4296c47 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 中文審定書 II
致謝 III 中文摘要 IV Abstract VI Introduction IX Tables of content 1 Chapter 2 6 UNC-5/netrin receptor promotes apoptosis through SRC-2 in response to UNC-129/TGF-β signal 6 Introduction 7 Materials and Methods 11 Strains 11 Cell death assays 11 Molecular Biology 11 Transgenic animals 12 Heat Shock Experiments 12 Bacteria-mediated RNAi 13 Yeast 2-hybrid experiment 13 Microscopy 13 Results 15 The loss of unc-5 causes reduced cell death in both somatic and germline cells 15 The loss of unc-5 enhances cell survival in weak ced-3 mutants 17 The overexpression of unc-5 results in ectopic cell deaths 19 UNC-5 functions and expresses in dying cells to promote apoptosis 20 UNC-5 responds to the external signal UNC-129 to induce apoptosis 21 UNC-129 needs to be secreted and acts cell-nonautonomously to promote cell death 22 SRC-2 physically interacts with the intracellular region of UNC-5 24 dapk-1 acts downstream of unc-5 to promote cell death 26 dapk-1 acts downstream of unc-5 to promote cell death 27 unc-5 likely acts upstream of or in parallel to ced-3 in promoting apoptosis 28 Discussion 31 The evolutionary conserved pro-apoptotic role of UNC-5 and the significance of this pathway 31 Multiple roles of unc-5 as pro-apoptotic receptor in cell-death and guidance receptor in cell-migration 32 Chapter 3 34 C. elegans EIF-3.K promotes programmed cell death through CED-3 caspase 34 Introduction 35 Materials and Methods 37 Strains 37 Cell death assays 37 Molecular Biology 38 Transgenic Animals 39 Heat Shock Experiments 40 Antibodies, immunostaining and Immunoblotting 41 Bacteria-mediated RNAi 42 Result 44 The loss of eif-3.K causes reduced cell death in both somatic and germline cells 44 The loss of eif-3.K enhances cell survival in sensitized mutants 46 The loss of eif-3.K partially suppresses the ectopic cell deaths induced by the overexpression of egl-1 or ced-4 49 eif-3.K acts upstream of ced-3 in the promotion of programmed cell death 52 eif-3.K promotes cell death in a cell-autonomous fashion 53 The loss of eif-3.K significantly reduces ectopic cell deaths in icd-1 mutants 53 EIF-3.K is widely expressed throughout embryogenesis and localized to the cytoplasm 54 The WH domain of EIF-3.K is necessary and sufficient for its cell death-promoting activity 55 Human eIF3k can partially substitute for C. elegans EIF-3.K 57 Discussion 58 The pro-apoptotic function of EIF-3.K is conserved through evolution 58 CED-3 caspase dependent programmed cell death 58 EIF-3.K act with the intermediate filaments during apoptosis 62 WH domain carries pro-apoptotic function 63 Referance 65 Figures 76 Figure 1. A loss of unc-5 reduce cell corpse number in the germline. 76 Figure 2. A loss of unc-129 reduce cell corpse number and the expression of UNC-129 in muscle cells rescue the cell death defect in the germline. 77 Figure 3. The identification of extraneous surviving cells in the unc-5 mutants. 78 Figure 4. The UNC-5::GFP is found to express on dying cells during early and mid embryogenesis. 79 Figure 5. UNC-129::GFP on cytoplasm and UNC-129(ΔSP)::GFP not be detected on cytoplasm. 80 Figure 6. The Psrc-2::GFP is found to express on dying cells during embryo and larva stage. 81 Figure 7. SRC-2 interacts with the intracellular region of UNC-5 in the yeast two-hybrid assay. 82 Figure 8. DAPK-1 but not DAPK-1ΔDD interacts with the SRC-2 in the yeast two-hybrid assay. 83 Figure 9. UNC-129 ligand, UNC-5 receptor, SRC-2 and DAPK-1 together define a novel extrinsic apoptosis pathway in worms. 84 Figure 10. eif-3.K has been conserved throughout evolution. 85 Figure 11. EIF-3.K protein expression. 86 Figure 12. The loss of eif-3.K results in reduced programmed cell deaths. 87 Figure 13. The loss of eif-3.K reduces TUNEL staining. 88 Figure 14. A loss of eif-3.K reduces cell corpse number in the germline. 89 Figure 15. A loss of eif-3.K increases the number of extra surviving cells in weak ced-3 mutants. 90 Figure 16. The loss of eif-3.K partially suppresses cell death induced by the overexpression of egl-1. 91 Figure 17. The loss of eif-3.K partially suppresses cell death induced by the overexpression of ced-4. 92 Figure 18. The loss of eif-3.K dose not suppresses cell death induced by the overexpression of ced-3. 93 Figure 19. The loss of eif-3.K partially suppresses cell death induced by the overexpression of egl-1and ced-4, but not ced-3. 94 Figure 20. eif-3.K partially suppresses the ectopic cell deaths caused by the loss of icd-1. 95 Figure 21. The identification of extraneous surviving cells in the eif-3.K mutants. 96 Figure 22. EIF-3.K is not associated with mitochondria. 97 Figure 23. Deletion of the WH domain does not affect the expression pattern or stability of EIF-3.K. 98 Figure 24. Neither EIF-3.K nor the WH domain alone interacts with CED-3 or CED-4 in a yeast 2-hybrid assay. 99 Figure 25. Loss of eif-3.K reduced DNA damage-induced apoptosis. 100 Figure 26. Loss of eif-3.K suppressed the increased cell death phenotype of csp-2 mutants in the germline. 101 Tables 102 Table 1. The loss of unc-5, unc-129, src-2, and dapk-1 results in reduced programmed cell deaths. 102 Table 2. The cell corpse numbers in the mutants defective in genes encoding DD-containing proteins. 103 Table 3. A loss of unc-5 increases the number of extra surviving cells in weak ced-3 mutants. 104 Table 4. Overexpression of unc-5, unc-129 and dapk-1 in cell death-defective mutants. 105 Table 5. unc-6, unc-40, TGF-β-like genes and src-1 are not required for embryonic cell deaths. 107 Table 6. Effect of src-2 overexpression on programmed cell death. 108 Table 7. The loss of eif-3.K enhances cell survival in the ventral cord of sensitized mutants. 109 Table 8. Overexpression of eif-3.K or ced-3 in cell death-defective mutants. 110 Table 9. Structure and function analysis of eif-3.K. 111 Table 10. eif-3.K is not essential for embryonic or larval development. 112 Table 11. The missing cell defect in csp-3 mutants was suppressed by loss of eif-3.K. 113 | |
| dc.language.iso | en | |
| dc.subject | 線蟲 | zh_TW |
| dc.subject | 計畫性細胞死亡 | zh_TW |
| dc.subject | unc-5 | en |
| dc.subject | eif-3.K | en |
| dc.title | 描述線蟲unc-5與eif-3.K在計畫性細胞死亡中的功能 | zh_TW |
| dc.title | Characterization of unc-5 and eif-3.K in C. elegans programmed cell death | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳瑞華(Ruey-Hwa Chen),陳俊宏(Chun-Hong Chen),潘俊良(Chun-Liang Pan),廖秀娟 | |
| dc.subject.keyword | 線蟲,計畫性細胞死亡, | zh_TW |
| dc.subject.keyword | unc-5,eif-3.K, | en |
| dc.relation.page | 113 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-08-20 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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