臺灣博碩士論文加值系統

在生物發育的過程中，器官的大小會維持在固定的大小，而個體也會隨時偵測體內器官的大小是否正常，這個現象對生物學家而言相當的有趣。然而，某些不正常的組織生長--如腫瘤的生成--必須先破壞偵測大小的機制，進而讓組織有機會過度生長。以哺乳動物的肝臟為例，在手術切除部份之後肝臟可以重新生長回到原本的大小，這暗示了偵測器官大小的機制存在並且可以調整器官大小的不正常。因此，我以果蠅的脂肪體作為研究的對象，希望透過對脂肪體大小調控機制的了解，進一步了解細胞與器官大小的調控，同時也可以更加了解腫瘤形成的原因。
果蠅的脂肪體在生理功能與發育過程中都與肝臟有許多類似的部份，所以我以馬賽克分析的技術在果蠅中胚層的部份細胞中大量表現特定的基因，若此基因影響細胞大小過量表現這個基因的細胞大小也會改變。透過這個系統我猜選了535個品系的果蠅並到六個基因--Set, RacI, CG18005, CG3679, CG4963 and
Trithorax. 因為Set在果蠅中的新穎性，同時Set在演化中被高度的保留也顯示了他的重要性，所以我選擇Set基因做後續的研究。
Set最早在人類的急性白血病患者身上被發現，並且被認定是一個致癌基因。當我將Set過量表現在脂肪體的部份細胞中，可以發現細胞大小增加了20%，如果在飢餓的狀態下大小更增加了33%。同時我以MS1096將SET過量表現在翅成蟲盤的背側，可以發現分裂中的細胞數目有明顯的增加，顯示SET讓細胞週期加速進行；而已TUNEL偵測細胞凋亡的現象，則發現細胞凋亡的數目沒有顯著的變化。這三個結果顯示Set在果蠅的脂肪體內可能透過同時增加單一細胞大小與細胞分裂的速度來影響組織大小的調控。若以hs-GAL4過量表現在全身細胞中，果蠅的三齡幼蟲在誘發GAL4之後約48小時會出現黑色素團塊並死亡，這個現象與誘發其他致癌基因如E2F的結果相類似，證明Set在果蠅中應該也可扮演致癌基因的角色。

Constant size of organs has been fascinated by biologists. During development, embryos are able to sense organ size change and regulate proliferation rate or volume of cells. However, tumor cells must escape from this size control. To get more insight how hepatoma develops, size control of liver is one of important aspects to be investigated. The single layer of cells composed of Drosophila fat body serves as a nice model system because it is not only its physiology functions, but its development in body cavity is similar to those in vertebrate liver.
To screen genes controlling size of Drosophila fat body, I set up a transgenic fly line, act>y+>GAL4, UAS-GFP; twi-FLP used to cross with males containing P{EP} or P{EPgy2} transgene. In organs derived from mesoderm, if FLP flipped out the y+ between two FRTs, GAL4 is driven by the actin promoter. Then, GAL4 drives expression of genes at 3’ end of P{EP} or P{EPgy2}. By screening 535 P{EP} or P{EPgy2} lines, I obtained 6 candidates - Set, RacI, CG18005, CG3679, CG4963 and Trithorax. Due to the novelty and evolution conservation, I chose Set to study further.
SET was first identified as a CAN-fusion protein in acute leukemia and been reported to promote cell cycle by binding to CyclinE/Cdk2 inhibitor, p21. To determine whether Set is involved in the size control, cells in fat-body clones with overexpression of Set is 20 and 33% bigger than adjacent cells in normal nutrient condition and amino acid starvation, respectively. Similarily, in wing disc, cell number increase in dorsal side if SET is overexpressed by MS1096-GAL4 in dorsal. Number of dead ells is insignificantly different from those in the ventral of the disc using the TUNEL assay. Furthermore, ubiquitous express SET by hs-GAL4 in larva induced melanoma-like tumor, consistent with that in clones expressing other oncogenes. In conclusion, Set stimulates coordinately cell growth and cell proliferation in larva fat body. Thus, it is likely that Set is involved in the size control of fat body.

中文摘要 4
Abstract: 5
Introduction: 7
Materials and Methods 17
Results 25
Discussion: 30
Reference 33
Figures and Tables 44

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Adachi, Y., Pavlakis, G.N., and Copeland, T.D. 1994a. Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia. The Journal of biological chemistry 269(3): 2258-2262.
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Adler, H.T., Nallaseth, F.S., Walter, G., and Tkachuk, D.C. 1997. HRX leukemic fusion proteins form a heterocomplex with the leukemia-associated protein SET and protein phosphatase 2A. The Journal of biological chemistry 272(45): 28407-28414.
Al-Murrani, S.W., Woodgett, J.R., and Damuni, Z. 1999. Expression of I2PP2A, an inhibitor of protein phosphatase 2A, induces c-Jun and AP-1 activity. The Biochemical journal 341 ( Pt 2): 293-298.
Bellen, H.J., Levis, R.W., Liao, G., He, Y., Carlson, J.W., Tsang, G., Evans-Holm, M., Hiesinger, P.R., Schulze, K.L., Rubin, G.M., Hoskins, R.A., and Spradling, A.C. 2004. The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167(2): 761-781.
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Canela, N., Rodriguez-Vilarrupla, A., Estanyol, J.M., Diaz, C., Pujol, M.J., Agell, N., and Bachs, O. 2003. The SET protein regulates G2/M transition by modulating cyclin B-cyclin-dependent kinase 1 activity. The Journal of biological chemistry 278(2): 1158-1164.
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Canela, N., Rodriguez-Vilarrupla, A., Estanyol, J.M., Diaz, C., Pujol, M.J., Agell, N., and Bachs, O. 2003. The SET protein regulates G2/M transition by modulating cyclin B-cyclin-dependent kinase 1 activity. The Journal of biological chemistry 278(2): 1158-1164.
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Dang, D.T. and Perrimon, N. 1992. Use of a yeast site-specific recombinase to generate embryonic mosaics in Drosophila. Developmental genetics 13(5): 367-375.
Dolezal, T., Dolezelova, E., Zurovec, M., and Bryant, P.J. 2005. A role for adenosine deaminase in Drosophila larval development. PLoS biology 3(7): e201.
Epstein, C.J., Martin, G.M., Schultz, A.L., and Motulsky, A.G. 1966. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine 45(3): 177-221.
Fan, Z., Beresford, P.J., Oh, D.Y., Zhang, D., and Lieberman, J. 2003. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112(5): 659-672.
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Fukukawa, C., Shima, H., Tanuma, N., Ogawa, K., and Kikuchi, K. 2000. Up-regulation of I-2(PP2A)/SET gene expression in rat primary hepatomas and regenerating livers. Cancer letters 161(1): 89-95.
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Hoffmann, J.A., Reichhart, J.M., and Hetru, C. 1996. Innate immunity in higher insects. Current opinion in immunology 8(1): 8-13.
Hoshizaki, D.K., Blackburn, T., Price, C., Ghosh, M., Miles, K., Ragucci, M., and Sweis, R. 1994. Embryonic fat-cell lineage in Drosophila melanogaster. Development (Cambridge, England) 120(9): 2489-2499.
Huang, J., Wu, S., Barrera, J., Matthews, K., and Pan, D. 2005. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122(3): 421-434.
Janssens, V. and Goris, J. 2001. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. The Biochemical journal 353(Pt 3): 417-439.
Jiang, J., Cai, H., Zhou, Q., and Levine, M. 1993. Conversion of a dorsal-dependent silencer into an enhancer: evidence for dorsal corepressors. The EMBO journal 12(8): 3201-3209.
Justice, R.W., Zilian, O., Woods, D.F., Noll, M., and Bryant, P.J. 1995. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes & development 9(5): 534-546.
Kawamura, K., Shibata, T., Saget, O., Peel, D., and Bryant, P.J. 1999. A new family of growth factors produced by the fat body and active on Drosophila imaginal disc cells. Development (Cambridge, England) 126(2): 211-219.
Kellogg, D.R., Kikuchi, A., Fujii-Nakata, T., Turck, C.W., and Murray, A.W. 1995. Members of the NAP/SET family of proteins interact specifically with B-type cyclins. The Journal of cell biology 130(3): 661-673.
LaBaer, J., Garrett, M.D., Stevenson, L.F., Slingerland, J.M., Sandhu, C., Chou, H.S., Fattaey, A., and Harlow, E. 1997. New functional activities for the p21 family of CDK inhibitors. Genes & development 11(7): 847-862.
Li, M., Guo, H., and Damuni, Z. 1995. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry 34(6): 1988-1996.
Li, M., Makkinje, A., and Damuni, Z. 1996. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. The Journal of biological chemistry 271(19): 11059-11062.
Michalopoulos, G.K. and DeFrances, M.C. 1997. Liver regeneration. Science (New York, NY 276(5309): 60-66.
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Mirth, C.K. and Riddiford, L.M. 2007. Size assessment and growth control: how adult size is determined in insects. Bioessays 29(4): 344-355.
Nagasue, N., Kohno, H., Hayashi, T., Yamanoi, A., Uchida, M., Takemoto, Y., Makino, Y., Ono, T., Hayashi, J., and Nakamura, T. 1993. Lack of intratumoral heterogeneity in DNA ploidy pattern of hepatocellular carcinoma. Gastroenterology 105(5): 1449-1454.
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