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研究生:蔣沆祥
研究生(外文):Hang-Shiang Jiang
論文名稱:表皮生長因子與PYR-1在線蟲中影響特定細胞凋亡的機制研究
論文名稱(外文):Characterization of EGF signaling and PYR-1 in the death of specific cells in C. elegans
指導教授:吳益群
口試委員:陳昌熙黃筱鈞潘俊良吳瑞菁陳俊宏
口試日期:2014-07-09
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:分子與細胞生物學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:143
中文關鍵詞:表皮生長因子計畫性細胞凋亡線蟲
外文關鍵詞:Epidermal growth factorprogrammed cell deathC. elegans
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計畫性細胞凋亡在生物體發育上扮演重要的角色。儘管執行計畫性細胞凋亡的基因已被發現且研究許多,這些基因如何在生物發育過程中被啟動與調控仍然有待發掘。我們發現在線蟲中,表皮生長因子〈LIN-3/EGF〉會以一種外來訊號的方式促進特定細胞的計畫性細胞凋亡。過少的EGF會導致計畫性細胞凋亡的減少;反之,過多的EGF會導致計畫性細胞凋亡的增加。這表示在生物體中,EGF必須保持在一個適當的濃度以確保適度的計畫性細胞凋亡進行。藉由遺傳分析,我們發現EGF會藉由上皮生長因子受器〈LET-23/EGFR〉活化下游Mitogen-Activated Protein Kinase〈MAPK〉路徑以及ETS轉錄因子〈LIN-1〉來促進線蟲中的BH3-only基因〈egl-1〉的轉錄並進一步引起特定細胞中的計畫性細胞凋亡。利用即時定量聚合&;#37238;連鎖反應和活體螢光觀測,我們發現在EGF的突變株中,egl-1的轉錄量會減少。更進一步地,利用凝膠遷移實驗〈EMSA〉以及異位表現基因的方式,我們證明了LIN-1可以直接結合到egl-1的啟動子上,而且這個結合對於表皮生長因子在活體中促進計畫性細胞凋亡來說是重要的。這些結果說明了表皮生長因子可以藉由提升egl-1的轉錄來促進特定計畫性細胞凋亡。

為了進一步找出在線蟲中參與計畫性細胞凋亡的調控因子,我們將grp-1突變株處理突變劑並找尋具有尾巴缺陷的突變株。GRP-1是一種ARF家族的GTP交換因子,當其和計畫性細胞凋亡相關基因同時產生突變時,突變株會展現尾巴缺陷的現象。藉由這個方式,我們找到了182個突變株,其中含有已知的計畫性細胞凋亡基因,如egl-1、ced-4、ced-3、ced-8和ced-11。除此之外,我們亦發現了PYR-1在線蟲中具有促進計畫性細胞凋亡的功能。這些結果顯示此基因掃描是具有其可行性。PYR-1是人類CAD (carbamoyl phosphate synthetase、aspartate transcarbamylase與dihydroorotase)的同源基因,參與在合成嘧啶的速率決定步驟。我們發現PYR-1影響到表皮細胞hyp8/9及分泌細胞excretory cell的姨細胞計畫性細胞凋亡,而且這個促進計畫性細胞凋亡的功能和其合成嘧啶的功能並不相關。除此之外,我們亦發現PYR-1是CED-3的&;#37238;作用物。因此,藉由這個基因掃描,我們找到了新的計畫性細胞凋亡相關基因並且初步了解其機制。


Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. We found that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor LET-23 reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK-1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life-versus-death fate. Our data and the previous cell culture studies that EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans.

To identify new genes involved in PCD in C. elegans, we conducted a genetic screen for mutants with a high penetrance of tail defects in the grp-1 background. grp-1 encodes a GTP exchange factor for ARFs and mutations defective in the activation, execution, or kinetics of PCD act synergistically with the grp-1 mutation to cause abnormal tail morphology. From this screen, we isolated 182 mutants. These mutants are classified into three subgroups, depending on their cell-corpse profiles: reduced/delayed, elevated and unchanged cell corpse numbers during embryogenesis. By SNP mapping and complementation tests, 22 mutations isolated were localized in known ced genes. This result showed that this screen is feasible to identify genes important for PCD. In addition, we have isolated pyr-1, encoding C. elegans CAD (carbamoyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase). In mammals, CAD has been reported to control the rate-limiting step during pyrimidine biosynthesis. We found that pyr-1 promotes the PCD of the aunt cells of hyp8/9 and excretory cell and this cell death-promoting function is independent of its CAD activity. Moreover, we showed that PYR-1 is a substrate of CED-3 in vitro. Therefore, we identified a previously unassigned pro-apoptotic function of PYR-1.


摘要 i
ABSTRACT iii
TABLE OF CONTENTS v
Chapter 1. LIN-3/EGF Promotes the Programmed Cell Death of Specific Cells in C. elegans by Transcriptional Activation of the Pro-apoptotic Gene egl-1 1
INTRODUCTION 3
MATERIALS AND METHODS 7
General Methods and Strains 7
RNA interference (RNAi) 7
Transgenic animals 8
Heat shock treatment 9
Molecular biology 10
Cell death assays 11
Quantitative real-time reverse transcriptase (RT)-PCR 12
Quantification of Pegl-1::gfp intensity in ABprpppapp 12
Prediction of potential LIN-1 binding sites 13
Electrophoretic mobility shift assay (EMSA) 14
Statistical analysis 15
RESULTS 17
lin-3 and let-23 promote specific PCDs in C. elegans 17
Overexpression of lin-3 cause ectopic cell deaths 20
let-23 is expressed in dying cells, including ABpl/rpppapp 21
LIN-3 can act as an extrinsic signal to promote PCD 22
lin-3 signaling up-regulates egl-1 transcription 23
LET-23 transduces the cell death-promoting signal via the LET-60-MPK-1 pathway 25
LET-23 transduces the cell death-promoting signal via the transcription factor LIN-1, but not LIN-31 26
LIN-1 activates egl-1 transcription by direct binding to the egl-1 promoter 27
DISCUSSION 31
LIN-3 signaling promotes PCD through LET-60-MPK-1 signaling and LIN-1 to activate egl-1 transcription 31
An appropriate level of extrinsic LIN-3 signaling is important for the precise fine-tuning of the life-versus-death fate of cells 36
The LET-60-MPK-1 pathway promotes germline and developmental cell deaths 38
Pathological and physiological roles of EGFR in promoting cell death 39
REFERENCES 41
FIGURES AND TABLES 53
Figure 1. lin-3 and let-23 promote specific PCDs in C. elegans 54
Figure 2. Overexpression of lin-3 induces ectopic gland cell death(s) through let-23 and the core PCD pathway 57
Figure 3. let-23 is expressed in dying cells, whereas lin-3 acts in a cell-nonautonomous manner to promote PCD 60
Figure 4. lin-3 promotes egl-1 transcription 64
Figure 5. lin-3, lin-1 and the LET-60-MPK-1 pathway act in the same pathway to promote PCD 65
Figure 6. lin-3 promotes PCD through transcriptional activation of egl-1 by LIN-1 67
APPENDIX 71
Appendix 1. Loss of lin-3 causes the disappearance of ABpl/rpppapp corpse(s) 71
Appendix 2. The lin-3(e1417) mutation does not affect the duration of the first 13 cell corpses derived from the AB lineage 73
Appendix 3. Analysis of extra surviving cells in the pharyngeal region in the ced-3(n2427) seneitized background 75
Appendix 4. lin-3 requires let-23 and the core PCD pathway to incerase numbers of embryonic cell corpses 77
Appendix 5. Mutants defective in the LET-60-MPK-1 pathway have reduced numbers of cell corpses 79
Appendix 6. The PI3K pathway and PLC genes are not involved in embryonic PCD 81
Appendix 7. lin-1 mutants, but not lin-31 mutants, have reduced numbers of cell corpses 83
Chapter 2. Identify New Genes Involved in Programmed Cell Death in C. elegans 85
INTRODUCTION 87
MATERIALS AND METHODS 89
General Methods and Strains 89
Transgenic animals 89
Molecular biology 90
Cell death assays 90
Mutagenesis screen 91
Statistical analysis 92
RESULTS 93
Defects in the activation, execution, or kinetics of PCD cause the tail defect in the grp-1 background 93
Extra hyp8/9 results in the tail defect 94
Identify new genes involved in PCD by a genetic screen in the grp-1 background 96
45 mutants with reduced or delayed cell corpse profiles are isolated. 97
16 mutants with increased numbers of cell corpses are isolated 97
99 mutants with normal cell corpse numbers are isolated 98
pyr-1 is isolated as a new PCD gene 99
DISCUSSION 103
Extra hyp8/9 causes the tail defect in the grp-1; ced-3 mutants 103
A genetic screen in the grp-1 sensitized background can isolate PCD-defective mutations 104
Mutants with abnormal tail morphogenesis independent of PCD can also be isolated from this genetic screen 105
REFERENCES 107
FIGURES AND TABLES 111
Figure 1. A model illustrates how the grp-1 and ced-3 mutations may act synergistically to result in extra neurons 111
Figure 2. The grp-1(gm350); ced-3(n717) double mutant displays abnormal tail morphology 113
Figure 3. The grp-1; ced-3 double mutant has ventral ridge(s) posterior to the anus 115
Figure 4. The grp-1; ced-3 mutant has extra hyp8/9 and PHsh 118
Figure 5. Extra hyp8/9 is sufficient to cause the tail defect 119
Figure 6. The proposed lineages in worms of the indicated genotypes 121
Figure 7. The flowchart and brief description of a genetic screen to isolate mutants with tail defects in the grp-1 sensitized background 123
Figure 8. PYR-1 can be cleaved by CED-3 in vitro and is important in the PCD of the aunt cells of hyp8/9 and excretory cell 125
Figure 9. The expression pattern of pyr-1 127
Table 1. Defects in the induction, execution, or kinetics of PCD cause tail defects in the grp-1 background. 129
Table 2. Mutants with known ced genes (22 mutants) 131
Table 3. Mutants with reduced or delayed cell corpse profiles (45 mutants) 133
Table 4. Mutants with increased numbers of cell corpses (16 mutants) 135
Table 5. Mutants with unchanged numbers of cell corpses (grp-1-dependent, 39 mutants) 137
Table 6. Mutants whose tail defects are grp-1-independent (24 mutants). 139
Table 7. Unanalyzed mutants (36 mutants) 141
APPENDIX 143
Appendix 1. A proposed lineage in the mutants with both tail defects and increased numbers of cell corpses. 143


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Chapter 2
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