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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 吳益群 | |
dc.contributor.author | Huang-Chin Lin | en |
dc.contributor.author | 林皇芹 | zh_TW |
dc.date.accessioned | 2021-06-16T05:34:14Z | - |
dc.date.available | 2024-12-31 | |
dc.date.copyright | 2014-08-17 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-13 | |
dc.identifier.citation | 1. Chiang, M.F., Yang, S.Y., Lin, I.Y., Hong, J.B., Lin, S.J., Ying, H.Y., Chen, C.M., Wu, S.Y., Liu, F.T., and Lin, K.I. (2013). Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice. Proc Natl Acad Sci U S A 110, 6476-6481.
2. Chiorazzi, M., Rui, L., Yang, Y., Ceribelli, M., Tishbi, N., Maurer, C.W., Ranuncolo, S.M., Zhao, H., Xu, W., Chan, W.-C.C., et al. (2013). Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma. Proceedings of the National Academy of Sciences, 1217271110. 3. Fielenbach, N., Guardavaccaro, D., Neubert, K., Chan, T., Li, D., Feng, Q., Hutter, H., Pagano, M., and Antebi, A. (2007). DRE-1: an evolutionarily conserved F box protein that regulates C. elegans developmental age. Dev Cell 12, 443-455. 4. Fuchs, Y., and Steller, H. (2011). Programmed cell death in animal development and disease. Cell 147, 742-758. 5. Gerstein, M.B., Lu, Z.J., Van Nostrand, E.L., Cheng, C., Arshinoff, B.I., Liu, T., Yip, K.Y., Robilotto, R., Rechtsteiner, A., Ikegami, K., et al. (2010). Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775-1787. 6. Hengartner, M.O., and Horvitz, H.R. (1994a). Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318-320. 7. Hengartner, M.O., and Horvitz, H.R. (1994b). C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665-676. 8. Hoeppner, D.J., Hengartner, M.O., and Schnabel, R. (2001). Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202-206. 9. Horn, M., Geisen, C., Cermak, L., Becker, B., Nakamura, S., Klein, C., Pagano, M., and Antebi, A. (2014). DRE-1/FBXO11-Dependent Degradation of BLMP-1/BLIMP-1 Governs C. elegans Developmental Timing and Maturation. Developmental Cell 28, 697-710. 10. Horsley, V., O'Carroll, D., Tooze, R., Ohinata, Y., Saitou, M., Obukhanych, T., Nussenzweig, M., Tarakhovsky, A., and Fuchs, E. (2006). Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126, 597-609. 11. Huang, T.F., Cho, C.Y., Cheng, Y.T., Huang, J.W., Wu, Y.Z., Yeh, A.Y., Nishiwaki, K., Chang, S.C., and Wu, Y.C. (2014). BLMP-1/Blimp-1 Regulates the Spatiotemporal Cell Migration Pattern in C. elegans. PLoS Genet 10, e1004428. 12. Keller, A.D., and Maniatis, T. (1992). Only two of the five zinc fingers of the eukaryotic transcriptional repressor PRDI-BF1 are required for sequence-specific DNA binding. Mol Cell Biol 12, 1940-1949. 13. Knodel, M., Kuss, A.W., Lindemann, D., Berberich, I., and Schimpl, A. (1999). Reversal of Blimp-1-mediated apoptosis by A1, a member of the Bcl-2 family. Eur J Immunol 29, 2988-2998. 14. Lettre, G., and Hengartner, M.O. (2006). Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol 7, 97-108. 15. Lin, F.R., Kuo, H.K., Ying, H.Y., Yang, F.H., and Lin, K.I. (2007). Induction of apoptosis in plasma cells by B lymphocyte-induced maturation protein-1 knockdown. Cancer Res 67, 11914-11923. 16. Magnusdottir, E., Kalachikov, S., Mizukoshi, K., Savitsky, D., Ishida-Yamamoto, A., Panteleyev, A.A., and Calame, K. (2007). Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc Natl Acad Sci U S A 104, 14988-14993. 17. Maurer, C.W., Chiorazzi, M., and Shaham, S. (2007). Timing of the onset of a developmental cell death is controlled by transcriptional induction of the C. elegans ced-3 caspase-encoding gene. Development 134, 1357-1368. 18. Messika, E.J., Lu, P.S., Sung, Y.J., Yao, T., Chi, J.T., Chien, Y.H., and Davis, M.M. (1998). Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J Exp Med 188, 515-525. 19. Metzstein, M.M., Stanfield, G.M., and Horvitz, H.R. (1998). Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet 14, 410-416. 20. Nehme, R., and Conradt, B. (2008). egl-1: a key activator of apoptotic cell death in C. elegans. Oncogene 27 Suppl 1, S30-40. 21. Rougvie, A.E. (2005). Intrinsic and extrinsic regulators of developmental timing: from miRNAs to nutritional cues. Development 132, 3787-3798. 22. Schmidt, D., Nayak, A., Schumann, J.E., Schimpl, A., Berberich, I., and Berberich-Siebelt, F. (2008). Blimp-1Deltaexon7: a naturally occurring Blimp-1 deletion mutant with auto-regulatory potential. Exp Cell Res 314, 3614-3627. 23. Schumacher, B., Schertel, C., Wittenburg, N., Tuck, S., Mitani, S., Gartner, A., Conradt, B., and Shaham, S. (2005). C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ 12, 153-161. 24. Shaham, S., and Horvitz, H.R. (1996). An Alternatively Spliced C. elegans ced-4 RNA Encodes a Novel Cell Death Inhibitor. Cell 86, 201-208. 24. Sulston, J.E., and Horvitz, H.R. (1977). Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56, 110-156. 25. Sulston, J.E., Schierenberg, E., White, J.G., and Thomson, J.N. (1983). The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100, 64-119. 26. Turner, C.A., Jr., Mack, D.H., and Davis, M.M. (1994). Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297-306. 27. Tseng, W.-C., 2012. Heterochronic genes, blmp-1 and dre-1, regulate tail-spike cell death in C. elegans, Master Dissertation, Institute of Molecular and Cellular Biology. National Taiwan University. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56548 | - |
dc.description.abstract | 計畫性細胞凋亡在生物發育及維持生理恆定扮演著重要的角色。在線蟲中,當egl-1/BH-3-only gene的轉錄作用啟動,會促進大部分的體細胞活化凋亡的訊息傳遞鏈進一步死亡。EGL-1表現量的提升進而使得CED-4從CED-4-CED-9複合物中釋放,活化了下游的CED-3,最終導致細胞死亡。儘管如此,依然存在著不同的機制來開啟特定細胞的凋亡核心路徑。一對坐落在尾部的尾突細胞於bean stage前出生,隨著時間的發育,兩顆尾突細胞進行質融合,產生一顆雙核的細胞,接著分化出由微管構成的支架結構,朝尾部延伸並且協助尾巴型態的正常發育,約略於3-fold至3.2-fold stage開始執行細胞凋亡,而在約3.2-fold至3.6-fold stage產生了尾突細胞的細胞屍體。相較於大部分出生後30分鐘內即會進行細胞凋亡的體細胞,對於尾突細胞在特定時間點啟動細胞凋亡的機制與主要的調控因子依然存在著許多未知。實驗室先前的研究發現blmp-1會影響某些胚胎時期的細胞凋亡,其中包含了尾突細胞。已知blmp-1屬於zinc finger transcriptional repressor,首先我們利用blmp-1::gfp的質體表現於ced-3(n717)突變株中。從3-fold stage至胚胎晚期,blmp-1開始表現在尾突細胞內,這意謂著blmp-1表現在尾突細胞中的時間點被嚴密地調控,同時blmp-1的表現對於細胞凋亡非常地重要。為了進一步釐清blmp-1與細胞凋亡之核心路徑中ced-3、ced-4和ced-9的調控關係,首先,我將CED-3專一性地過量表現於尾突細胞中,發現可以讓blmp-1突變株中不正常存活的尾突細胞進行凋亡,因此我們認為blmp-1導入凋亡的核心路徑,其作用位置可能是ced-3的上游或者平行於ced-3。有趣的是,將全長CED-4在高濃度情性下表現在wild type中會造成尾突細胞的不正常存活,之後會再更進一步地解開此非預期內的結果。接著,我觀察到,ced-9失去功能的情形下,可以部分的rescue blmp-1所造成的尾突細胞凋亡缺失,這意謂著blmp-1需要透過ced-9的功能來促進尾突細胞的凋亡。另一方面, Dr. Shai Shaham實驗室發現dre-1可能藉由負向調控ced-9的轉譯表現,最終促進尾突細胞的死亡。已知,dre-1是SCF E3 ubiquitin ligase 複合體中的 F-box protein,它的功能主要是協助辨識受質以利蛋白質降解的進行。而我藉由轉殖基因的方法,觀察到dre-1從bean至2-fold stage只會表現於尾突細胞中,其臨近的下皮細胞無表現,令人意外的是,dre-1突然在3-fold stage消失了,約略3.2-fold至3.6-fold stage又再度開始表現於尾突細胞內。這暗示著dre-1對於啟動尾突細胞凋亡時間點的調控也是相當地重要。有趣的是,將blmp-1過量表現於dre-1 (RNAi)突變株中,可以rescue因為dre-1表現量降低造成得尾突細胞不正常存活率。這樣的結果暗指blmp-1可能平行於dre-1或者作用在其下游的位置,最終促進尾突細胞的凋亡。綜合以上所述,我們觀察了blmp-1與dre-1在尾突細胞內時間與空間上的表現情形 ,並且指出在基因層次上,blmp-1與核心路徑中的ced-3以及ced-9之間的關係。 | zh_TW |
dc.description.abstract | Programmed cell death (PCD) plays an important role in animal development. In Caenorhabditis elegans, transcriptional up-regulation of egl-1/BH-3-only gene promotes most somatic cell deaths. The increased level of EGL-1 induces the release of the proapoptotic CED-4(Apaf-1) from the CED-4-CED-9 complex and hence activating the downstream CED-3 caspase. However, some cell deaths, such as tail-spike cell death, use alternative mechanisms to switch on the core PCD pathway, because egl-1 is not absolutely required for these deaths. Two tail-spike cells are generated in the tail region before the bean stage. They fuse to become a binuclear cell at the comma stage. The binuclear cell differentiates and extends a long, thin, microtubule-based spike to help tail elongation during later embryogenesis. The binuclear cell undergoes apoptosis at about the 3.2-fold to 3.6-fold stage, when tail morphogenesis is complete. The temporal regulation of tail-spike cell death is poorly understood. We found that blmp-1, which encodes a zinc finger transcriptional repressor, is required for the death of some embryonic cells, including that of tail-spike cell. Using the blmp-1 transcriptional GFP reporter in the ced-3(n717) mutant, the expression of blmp-1 was detected in the tail-spike cell from 3-fold to late embryogenesis stage. This result suggests that blmp-1 is transcriptional up-regulated prior to tail-spike cell death. We next examined the relationship of blmp-1 with the key PCD genes ced-3, ced-4 and ced-9. First, over-expression of ced-3 specifically in the tail-spike cell rescues the PCD defect in the blmp-1(s71) mutant, suggesting that blmp-1 acts upstream of, or in parallel to, ced-3 to promote tail-spike cell death. Intriguingly, over-expression of high dosage of the ced-4 full-length cDNA results in abnormal tail-spike cell survival in the wild type. Further experiment is maded to unravel this unexpected result. Second, loss of ced-9 partially suppresses the tail-spike cell death phenotype of the blmp-1(s71) mutant, suggesting that blmp-1 acts upstream of, or in parallel to ced-9. Dr. Shai Shaham lab found that dre-1, which encodes an F-box protein of an SCF (Skp1-Cullin-F-box protein) E3 ubiquitin ligase mediating protein degradation, promotes tail-spike cell death. Using transgenic approaches, we observed the expression of dre-1 disappeared suddenly in tail-spike cell at the 3-fold stage, but it reappeared at about the 3.2-fold to 3.6-fold stage, suggesting that dre-1 expression is also critical for timely tail-spike cell death. Interestingly, over-expression of blmp-1 can rescue the tail-spike cell death defect in the dre-1(RNAi) mutant, indicating blmp-1 may act downstream of, or in parallel to dre-1. Therefore, we have characterized the temporal expression pattern of blmp-1 and dre-1,and positioned blmp-1 genetically to core PCD genes ced-3 and ced-9. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T05:34:14Z (GMT). No. of bitstreams: 1 ntu-103-R01b43021-1.pdf: 1949052 bytes, checksum: aaa3395673f4a86098b3fb74c2718228 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 致謝 III
中文摘要 V Abstract VII Tables of content 1 Introduction 4 Materials and Methods 8 Nematode strains 8 Constructs 8 Transgenic worms 9 RNA interference (RNAi) 10 Quantification of GFP expression 11 Results 12 ced-3 expression disappeared at the 3-fold stage but reappeared in the tail-spike cell corpse 12 The expression of blmp-1coincides with the death of the tail-spike cell in the ced-3(n717) mutant 13 blmp-1 acts upstream of or in parallel to ced-3 to mediate tail-spike cell death 15 ced-4 cDNA over-expression results in abnormal tail-spike cell survival and abnormal expression pattern of Pcbr-ced-3::gfp in the wild type 15 blmp-1 functions to promote tail-spike cell death, at least in part, through ced-9 16 dre-1 expression in the tail-spike cell coincides with the death of the cell 17 blmp-1 may act downstream of or in parallel to dre-1 in tail-spike cell death 18 Discussion 20 Reactivation of ced-3 is important for tail-spike cell death 20 BLMP-1::GFP expression was still detected in tail-spike cell at the 4-fold stage 20 blmp-1 and dre-1 had different expression pattern before death timing in tail-spike cell 21 Rescue effect of ced-3 cDNA is different between the ced-3;tpIs6 mutant and the blmp-1(s71) mutant 22 The interaction of blmp-1 with ced-9 may be direct or indirect. 23 Model for blmp-1and dre-1-mediated tail-spike cell death 24 dre-1 may down-regulated blmp-1 25 The expression of BLMP-1 may not be higher in the dre-1 mutant. 26 References 28 Figures 32 Fig 1. Development of tail-spike cell at different stages. 33 Fig 2. PAL-1 and DRE-1mediate tail-spike cell death through the core programmed cell death pathway. 34 Fig 3. ced-3 expression disappeared at 3-fold stage was reappeared in the tail-spike cell corpse. 36 Fig 4. blmp-1 transcriptional reporter expressed in tail-spike cell from the 3-fold stage. 38 Fig 5. BLMP-1::GFP was expressed in the tail-spike cell from the 3-fold stage. 40 Fig 6. dre-1 transcriptional reporter was not expressed at the 3-fold stage but was reappeared at the time when tail-spike cell undergoes PCD. 42 Fig7. DRE-1::GFP expression was not detected at the 3-fold stage but was reappeared and correlated with the death in tail-spike cell. 44 Fig 8. BLMP-1 expression coincides with the timing of tail-spike cell death, and DRE-1 expression is much the same period as ced-3 expression in ced-3(n717) mutant. 45 Fig 9. Proposed model for blmp-1 and dre-1 mediate tail-spike cell death. 46 Tables 47 Table 1. Pcbr-ced-3(0.8kb) ::ced-3 (cDNA) rescued the tail-spike cell death defect in the ced-3(n717) mutant. 47 Table 2. Pcbr-ced-3(0.8kb) ::ced-3 (cDNA) rescued the tail-spike cell death defect in the blmp-1(s71) mutant. 48 Table 3. Pcbr-ced-3(0.8kb) ::ced-4S (cDNA) rescued the tail-spike cell death defect in the ced-4(n1162) mutan. 49 Table 4. Pcbr-ced-3(0.8kb) ::ced-4 (cDNA) results abnormal tail-spike cell survival that is dosage-dependent in wild type. 50 Table 5. Loss of blmp-1 required ced-9 to cause tail-spike cell survival. 51 Table 6. BLMP-1 over-expression partially rescued the tail-spike cell death defect in the dre-1(RNAi) mutant. 52 Supplementary data 53 Fig S1. BLMP-1::GFP expression was higher in the dre-1 (RNAi) mutant and the blmp-1(RNAi) mutant. 53 Table S1. dre-1 downregulates expression of blmp-1 in the ced-3 (n717) mutant. 54 | |
dc.language.iso | zh-TW | |
dc.title | 分析BLMP-1調控線蟲尾突細胞凋亡的功能 | zh_TW |
dc.title | Analyzing the function of BLMP-1 in tail-spike cell death in C. elegans | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 吳瑞菁,廖秀娟 | |
dc.subject.keyword | 細胞凋亡,尾突細胞,blmp-1,細胞凋亡核心路徑,dre-1, | zh_TW |
dc.subject.keyword | programmed cell death,tail-spike cell,blmp-1,core pathway,dre-1, | en |
dc.relation.page | 54 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-13 | |
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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