臺灣博碩士論文加值系統

Apoptin是一個由雞貧血病毒所產生的病毒蛋白， 已知會造成轉型細胞株的凋亡， 但對正常細胞卻無作用。 Apoptin誘發的細胞凋亡不需要p53蛋白的參與， 而且不會被Bcl-2所抑制， 因此Apoptin具有治療腫瘤的潛力， 特別是針對那些p53缺失或Bcl-2過度表現的腫瘤。 在轉型細胞株中， Apoptin位於細胞核內， 而Apoptin所造成的細胞凋亡， 也與其在細胞核的分佈有關。 我們認為瞭解Apoptin所造成的細胞凋亡機制， 將有助於未來在癌症治療上的應用。由我們的的研究中，以yeast two-hybrid之方法，分離到四種與Apoptin相互結合之蛋白， APAP1-4。由序列分析顯示APAP1為類似DEDAF，RYBP之蛋白，我們證實了APAP1與Apoptin在in vivo以及在in vitro可以相互結合。APAP1 為一個核蛋白，且將APAP1與Apoptin共同表現於 HeLa cell 中，他們會共同分佈於細胞核之位置，但於正常之HEL之細胞中，Apoptin主要分佈於細胞質中，僅有少量之Apoptin與APAP1分佈於細胞核之位置。若將APAP1大量表現於人類細胞則會造成細胞凋亡。 我們亦發現利用antisense APAP1來抑制內生性之APAP1，可以抑制由Apoptin所誘導之細胞凋亡，顯示APAP1在Apoptin所誘導之細胞凋亡過程中應扮演一定的角色。而 APAP1在腫瘤細胞株中比在正常細胞株中的表現量亦較高。APAP4為一類似Hippi之蛋白，Hippi為 Hip-1( Huntingtin interacting protein 1)之結合蛋白。而且Hip-1與Hippi均含有一類似DED之domain。我們證實APAP4/Hippi在in vivo以及在in vitro可以相互結合。我們亦發現Apoptin與APAP1以及APAP4結合之為區域是相同的，均位於Apoptin 的第1到第59個氨基酸之位置 。若將Apoptin以及APAP4共同表現於人類的細胞中，我們發現，Apoptin與APAP4在人類正常之HEL細胞中分佈細胞質內相同的區域，但於腫瘤的HeLa細胞中，則分佈於不同的區域。另外，我們也利用yeast two-hybrid assay之方法篩選到另一個與APAP4相互結合之蛋白，Nmi(N-myc/STAT interactor)，有趣的是Nmi已被發現在interferon調控之下會與IFP35蛋白結合，而IFP-35即為我們發現之另外一個Apoptin結合蛋白APAP3。我們也發現APAP4在正常細胞株比在腫瘤細株胞中之表現量為高。 在本論文中，我們主要針對了APAP1以及APAP4進行其功能之分析以及探討其在對於由Apoptin所誘導之細胞凋亡過程中所扮演之角色，並經由此一細胞凋亡機制的探討,了解Apoptin在臨床上可能之應用潛力.

A chicken anemia virus-derived protein VP-3 (Apoptin) was reported to cause apoptosis in human transformed cell lines but not in normal cells. Apoptosis induced by Apoptin is p53-independent and Bcl-2-insensitive, making Apoptin a potential agent for treatment of cancers, including those lacking p53 or overexpressing Bcl-2. However, the molecular mechanism of Apoptin-induced apoptosis has not yet been elucidated. In this study, we had identified four Apoptin-associated proteins, named APAP1, APAP2, APAP3 and APAP4, by yeast two-hybrid screening. Sequence analysis of APAP1 revealed that APAP1 is identical to DEDAF( death effector domain associated factor) and RYBP( Ring 1 and YY1 binding protein). DEDAF is a protein with the ability to interact with the death effector domains (DEDs) of caspase-8 and caspase-10. Sequence analysis of APAP4 revealed that APAP4 is identical to Hippi, a protein interactor of huntingtin interacting protein 1 (HIP-1). Interestingly, both HIP-1 and Hippi contain a domain with homology to DED. The binding of APAP1 and APAP4 to Apoptin in human cells was demonstrated by GST pull down assay and co-immunoprecipitation assays. Overexpression of APAP1 induced apoptosis in both cancerous HeLa cells and normal HEL cells, however less apoptotic toxicity was observed when HeLa and HEL cells were overexpressed with APAP4. Both APAP1 and APAP4 were bound to the identical region of Apoptin which was localized in the N terminus of a.a. 1-59. The immunofluorescence assay was performed to study the cellular localization of APAP1 and APAP4 in HeLa and HEL cells. APAP1 was localized mainly in the nuclear region of both cell lines, the colocalization of APAP1 and Apoptin was seen in the nucleus region of tumorous HeLa cells. However, only little amount of Apoptin was seen colocalized in the nucleus region of HEL cells. The colocalization of Apoptin and APAP4 was not observed. However, Apoptin and APAP4 were seen localized perfectly in HEL cells. The protein expression level of APAP1 and APAP4 was also studied. Higher APAP1 expression level was observed in various tumor cell lines compared to the normal cell lines. In contrast, the expression level of APAP4 was lower in the tumor cell lines compared to the normal cells. In addition, by using APAP4 as a bait for the further screening of APAP4-associated proteins, an N-myc interactor ( Nmi ) protein was identified. Interestingly, Nmi was also a binding partner of APAP3/IFP35, an interferon induced protein. In this study, by the cloning and characterization of the Apoptin associated proteins APAP1 and APAP4, we had proposed the possible roles of APAP1 and APAP4 in the apoptotic pathway induced by Apoptin in human tumor cells, and hopefully the suggested model will be beneficial for the clinical application of Apoptin.

第一章 細胞凋亡之簡介及歷史……………………………………………… 1
第二章 鷄貧血病毒 Apoptin 結合蛋白之篩選:酵母菌雙雜交分析 …… 15
第三章 Apoptin-Associated Protein 1參與細胞凋亡機制之探討 …… 27
第四章 Apoptin-Associated Protein 4參與細胞凋亡機制之探討 …… 54
第五章 綜合討論 …………………………………………………………… 70
參考文獻 ………………………………………………………………………… 74
附錄一 APAP1 cDNA ………………………………………………………… 88
附錄二 APAP2 cDNA ………………………………………………………… 90
附錄三 APAP3/IFP35 cDNA ………………………………………………… 98
附錄四 APAP4 cDNA ………………………………………………………… 100
附錄四 論文著述 …………………………………………………………… 103

參考文獻
Alnemri, E. S., Livingston, D. J., Nicholson, D. W., Salvesen, G., Thornberry, N. A., Wong, W. W., and Yuan, J. (1996). Human ICE/CED-3 protease nomenclature. Cell 87, 171.
Arends, M. J., Morris, R. G., and Wyllie, A. H. (1990). Apoptosis. The role of the endonuclease. Am J Pathol 136, 593-608.
Ashkenazi, A., and Dixit, V. M. (1998). Death receptors: signaling and modulation. Science 281, 1305-1308.
Avery, L., and 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.
Bange, F. C., Vogel, U., Flohr, T., Kiekenbeck, M., Denecke, B., and Bottger, E. C. (1994). IFP 35 is an interferon-induced leucine zipper protein that undergoes interferon-regulated cellular redistribution. J Biol Chem 269, 1091-1098.
Bergeron, L., Perez, G. I., Macdonald, G., Shi, L., Sun, Y., Jurisicova, A., Varmuza, S., Latham, K. E., Flaws, J. A., Salter, J. C., et al. (1998). Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12, 1304-1314.
Bienz, M., and Muller, J. (1995). Transcriptional silencing of homeotic genes in Drosophila. Bioessays 17, 775-784.
Boldin, M. P., Goncharov, T. M., Goltsev, Y. V., and Wallach, D. (1996). Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85, 803-815.
Boldin, M. P., Mett, I. L., Varfolomeev, E. E., Chumakov, I., Shemer-Avni, Y., Camonis, J. H., and Wallach, D. (1995a). Self-association of the "death domains" of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Biol Chem 270, 387-391.
Boldin, M. P., Varfolomeev, E. E., Pancer, Z., Mett, I. L., Camonis, J. H., and Wallach, D. (1995b). A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270, 7795-7798.
Butterworth, N. J., Williams, L., Bullock, J. Y., Love, D. R., Faull, R. L., and Dragunow, M. (1998). Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Neuroscience 87, 49-53.
Cerretti, D. P., Kozlosky, C. J., Mosley, B., Nelson, N., Van Ness, K., Greenstreet, T. A., March, C. J., Kronheim, S. R., Druck, T., Cannizzaro, L. A., and et al. (1992). Molecular cloning of the interleukin-1 beta converting enzyme. Science 256, 97-100.
Chen, J., and Naumovski, L. (2002). Intracellular redistribution of interferon-inducible proteins Nmi and IFP 35 in apoptotic cells. J Interferon Cytokine Res 22, 237-243.
Chen, J., Shpall, R. L., Meyerdierks, A., Hagemeier, M., Bottger, E. C., and Naumovski, L. (2000). Interferon-inducible Myc/STAT-interacting protein Nmi associates with IFP 35 into a high molecular mass complex and inhibits proteasome-mediated degradation of IFP 35. J Biol Chem 275, 36278-36284.
Chien, C. T., Bartel, P. L., Sternglanz, R., and Fields, S. (1991). The two-hybrid system: a method to identify and clone genes for proteins that interact with a protein of interest. Proc Natl Acad Sci U S A 88, 9578-9582.
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.
Chou, J. J., Matsuo, H., Duan, H., and Wagner, G. (1998). Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 94, 171-180.
Cohen, G. M. (1997). Caspases: the executioners of apoptosis. Biochem J 326 ( Pt 1), 1-16.
Cryns, V., and Yuan, J. (1998). Proteases to die for. Genes Dev 12, 1551-1570.
Danen-Van Oorschot, A. A., Fischer, D. F., Grimbergen, J. M., Klein, B., Zhuang, S., Falkenburg, J. H., Backendorf, C., Quax, P. H., Van der Eb, A. J., and Noteborn, M. H. (1997). Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells. Proc Natl Acad Sci U S A 94, 5843-5847.
Danen-van Oorschot, A. A., van Der Eb, A. J., and Noteborn, M. H. (2000). The chicken anemia virus-derived protein apoptin requires activation of caspases for induction of apoptosis in human tumor cells. J Virol 74, 7072-7078.
Danen-Van Oorschot, A. A., Zhang, Y., Erkeland, S. J., Fischer, D. F., van der Eb, A. J., and Noteborn, M. H. (1999). The effect of Bcl-2 on Apoptin in 'normal' vs transformed human cells. Leukemia 13 Suppl 1, S75-77.
Danno, K., and Horio, T. (1982). Formation of UV-induced apoptosis relates to the cell cycle. Br J Dermatol 107, 423-428.
DeGregori, J., Leone, G., Miron, A., Jakoi, L., and Nevins, J. R. (1997). Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A 94, 7245-7250.
Dorstyn, L., Colussi, P. A., Quinn, L. M., Richardson, H., and Kumar, S. (1999). DRONC, an ecdysone-inducible Drosophila caspase. Proc Natl Acad Sci U S A 96, 4307-4312.
Dragunow, M., Faull, R. L., Lawlor, P., Beilharz, E. J., Singleton, K., Walker, E. B., and Mee, E. (1995). In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport 6, 1053-1057.
Duan, H., and Dixit, V. M. (1997). RAIDD is a new 'death' adaptor molecule. Nature 385, 86-89.
Duncan, A. M., and Heddle, J. A. (1984). The frequency and distribution of apoptosis induced by three non-carcinogenic agents in mouse colonic crypts. Cancer Lett 23, 307-311.
Duvall, E., Wyllie, A. H., and Morris, R. G. (1985). Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56, 351-358.
Dyson, N. (1998). The regulation of E2F by pRB-family proteins. Genes Dev 12, 2245-2262.
Ellis, H. M., and Horvitz, H. R. (1986). Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817-829.
Ellis, R. E., Jacobson, D. M., and Horvitz, H. R. (1991). Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129, 79-94.
Ferguson, D. J., and Anderson, T. J. (1981). Morphological evaluation of cell turnover in relation to the menstrual cycle in the "resting" human breast. Br J Cancer 44, 177-181.
Fernandes-Alnemri, T., Armstrong, R. C., Krebs, J., Srinivasula, S. M., Wang, L., Bullrich, F., Fritz, L. C., Trapani, J. A., Tomaselli, K. J., Litwack, G., and Alnemri, E. S. (1996). In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci U S A 93, 7464-7469.
Fernandes-Alnemri, T., Litwack, G., and Alnemri, E. S. (1994). CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem 269, 30761-30764.
Fernandes-Alnemri, T., Litwack, G., and Alnemri, E. S. (1995a). Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family. Cancer Res 55, 2737-2742.
Fernandes-Alnemri, T., Takahashi, A., Armstrong, R., Krebs, J., Fritz, L., Tomaselli, K. J., Wang, L., Yu, Z., Croce, C. M., Salveson, G., and et al. (1995b). Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer Res 55, 6045-6052.
Fesus, L. (1991). Apoptosis fashions T and B cell repertoire. Immunol Lett 30, 277-282.
Fesus, L., and Thomazy, V. (1988). Searching for the function of tissue transglutaminase: its possible involvement in the biochemical pathway of programmed cell death. Adv Exp Med Biol 231, 119-134.
Fields, S., and Song, O. (1989). A novel genetic system to detect protein-protein interactions. Nature 340, 245-246.
Flinterman, M., Gaken, J., Farzaneh, F., and Tavassoli, M. (2003). E1A-mediated suppression of EGFR expression and induction of apoptosis in head and neck squamous carcinoma cell lines. Oncogene 22, 1965-1977.
Garcia, E., Marcos-Gutierrez, C., del Mar Lorente, M., Moreno, J. C., and Vidal, M. (1999). RYBP, a new repressor protein that interacts with components of the mammalian Polycomb complex, and with the transcription factor YY1. Embo J 18, 3404-3418.
Gervais, F. G., Singaraja, R., Xanthoudakis, S., Gutekunst, C. A., Leavitt, B. R., Metzler, M., Hackam, A. S., Tam, J., Vaillancourt, J. P., Houtzager, V., et al. (2002). Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 4, 95-105.
Goryo, M., Shibata, Y., Suwa, T., Umemura, T., and Itakura, C. (1987). Outbreak of anemia associated with chicken anemia agent in young chicks. Nippon Juigaku Zasshi 49, 867-873.
Green, D. R. (2000). Apoptotic pathways: paper wraps stone blunts scissors. Cell 102, 1-4.
Green, D. R., and Reed, J. C. (1998). Mitochondria and apoptosis. Science 281, 1309-1312.
Hakem, R., Hakem, A., Duncan, G. S., Henderson, J. T., Woo, M., Soengas, M. S., Elia, A., de la Pompa, J. L., Kagi, D., Khoo, W., et al. (1998). Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339-352.
Hengartner, M. O., Ellis, R. E., and Horvitz, H. R. (1992). Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494-499.
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.
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.
Hofmann, K., Bucher, P., and Tschopp, J. (1997). The CARD domain: a new apoptotic signalling motif. Trends Biochem Sci 22, 155-156.
Horvitz, H. R., Sternberg, P. W., Greenwald, I. S., Fixsen, W., and Ellis, H. M. (1983). Mutations that affect neural cell lineages and cell fates during the development of the nematode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol 48 Pt 2, 453-463.
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.
Huang, B., Eberstadt, M., Olejniczak, E. T., Meadows, R. P., and Fesik, S. W. (1996). NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384, 638-641.
Itoh, N., and Nagata, S. (1993). A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268, 10932-10937.
Itoh, N., Yonehara, S., Ishii, A., Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S. (1991). The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233-243.
Jeurissen, S. H., Wagenaar, F., Pol, J. M., van der Eb, A. J., and Noteborn, M. H. (1992). Chicken anemia virus causes apoptosis of thymocytes after in vivo infection and of cell lines after in vitro infection. J Virol 66, 7383-7388.
Kalchman, M. A., Koide, H. B., McCutcheon, K., Graham, R. K., Nichol, K., Nishiyama, K., Kazemi-Esfarjani, P., Lynn, F. C., Wellington, C., Metzler, M., et al. (1997). HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 16, 44-53.
Kennison, J. A. (1995). The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu Rev Genet 29, 289-303.
Kerr, J. F., Wyllie, A. H., and Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26, 239-257.
Kischkel, F. C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P. H., and Peter, M. E. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo J 14, 5579-5588.
Kowalik, T. F., DeGregori, J., Leone, G., Jakoi, L., and Nevins, J. R. (1998). E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ 9, 113-118.
Kuida, K., Haydar, T. F., Kuan, C. Y., Gu, Y., Taya, C., Karasuyama, H., Su, M. S., Rakic, P., and Flavell, R. A. (1998). Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325-337.
Kuida, K., Zheng, T. S., Na, S., Kuan, C., Yang, D., Karasuyama, H., Rakic, P., and Flavell, R. A. (1996). Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368-372.
Kumar, S. (1995a). ICE-like proteases in apoptosis. Trends Biochem Sci 20, 198-202.
Kumar, S. (1995b). Inhibition of apoptosis by the expression of antisense Nedd2. FEBS Lett 368, 69-72.
Kumar, S., and Harvey, N. L. (1995). Role of multiple cellular proteases in the execution of programmed cell death. FEBS Lett 375, 169-173.
Kumar, S., Kinoshita, M., Noda, M., Copeland, N. G., and Jenkins, N. A. (1994). Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme. Genes Dev 8, 1613-1626.
Kumar, S., White, D. L., Takai, S., Turczynowicz, S., Juttner, C. A., and Hughes, T. P. (1995). Apoptosis regulatory gene NEDD2 maps to human chromosome segment 7q34-35, a region frequently affected in haematological neoplasms. Hum Genet 95, 641-644.
Laster, S. M., Wood, J. G., and Gooding, L. R. (1988). Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol 141, 2629-2634.
Lazebnik, Y. A., Kaufmann, S. H., Desnoyers, S., Poirier, G. G., and Earnshaw, W. C. (1994). Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371, 346-347.
Lebrun, S. J., Shpall, R. L., and Naumovski, L. (1998). Interferon-induced upregulation and cytoplasmic localization of Myc-interacting protein Nmi. J Interferon Cytokine Res 18, 767-771.
Lee, N. D., Chen, J., Shpall, R. L., and Naumovski, L. (1999). Subcellular localization of interferon-inducible Myc/stat-interacting protein Nmi is regulated by a novel IFP 35 homologous domain. J Interferon Cytokine Res 19, 1245-1252.
Leliveld, S. R., Zhang, Y. H., Rohn, J. L., Noteborn, M. H., and Abrahams, J. P. (2002). Apoptin induces tumour-specific apoptosis as a random, globular multimer. J Biol Chem.
Lewis, M., Tartaglia, L. A., Lee, A., Bennett, G. L., Rice, G. C., Wong, G. H., Chen, E. Y., and Goeddel, D. V. (1991). Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci U S A 88, 2830-2834.
Li, H., and Yuan, J. (1999). Deciphering the pathways of life and death. Curr Opin Cell Biol 11, 261-266.
Li, P., Allen, H., Banerjee, S., Franklin, S., Herzog, L., Johnston, C., McDowell, J., Paskind, M., Rodman, L., Salfeld, J., and et al. (1995). Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 80, 401-411.
Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X. (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479-489.
Menke, A. L., Shvarts, A., Riteco, N., van Ham, R. C., van der Eb, A. J., and Jochemsen, A. G. (1997). Wilms' tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. Cancer Res 57, 1353-1363.
Meyerdierks, A., Denecke, B., Rohde, M., Taparowsky, E. J., and Bottger, E. C. (1999). A cytoplasmic structure resembling large protein aggregates induced by interferons. J Histochem Cytochem 47, 169-182.
Mittl, P. R., Di Marco, S., Krebs, J. F., Bai, X., Karanewsky, D. S., Priestle, J. P., Tomaselli, K. J., and Grutter, M. G. (1997). Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone. J Biol Chem 272, 6539-6547.
Miura, M., Zhu, H., Rotello, R., Hartwieg, E. A., and Yuan, J. (1993). Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75, 653-660.
Moroni, M. C., Hickman, E. S., Denchi, E. L., Caprara, G., Colli, E., Cecconi, F., Muller, H., and Helin, K. (2001). Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3, 552-558.
Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J. D., Zhang, M., Gentz, R., et al. (1996). FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell 85, 817-827.
Nagata, S. (1997). Apoptosis by death factor. Cell 88, 355-365.
Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffin, P. R., Labelle, M., Lazebnik, Y. A., and et al. (1995). Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37-43.
Noteborn, M. H., de Boer, G. F., van Roozelaar, D. J., Karreman, C., Kranenburg, O., Vos, J. G., Jeurissen, S. H., Hoeben, R. C., Zantema, A., Koch, G., and et al. (1991). Characterization of cloned chicken anemia virus DNA that contains all elements for the infectious replication cycle. J Virol 65, 3131-3139.
Noteborn, M. H., Todd, D., Verschueren, C. A., de Gauw, H. W., Curran, W. L., Veldkamp, S., Douglas, A. J., McNulty, M. S., van der, E. A., and Koch, G. (1994). A single chicken anemia virus protein induces apoptosis. J Virol 68, 346-351.
Olson, R. L., and Everett, M. A. (1975). Epidermal apoptosis: cell deletion by phagocytosis. J Cutan Pathol 2, 53-57.
Opalka, B., Dickopp, A., and Kirch, H. C. (2002). Apoptotic genes in cancer therapy. Cells Tissues Organs 172, 126-132.
Ona, V. O., Li, M., Vonsattel, J. P., Andrews, L. J., Khan, S. Q., Chung, W. M., Frey, A. S., Menon, A. S., Li, X. J., Stieg, P. E., et al. (1999). Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263-267.
Parnaik, R., Raff, M. C., and Scholes, J. (2000). Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Curr Biol 10, 857-860.
Petersen, A., Mani, K., and Brundin, P. (1999). Recent advances on the pathogenesis of Huntington's disease. Exp Neurol 157, 1-18.
Piacentini, M., Fesus, L., Farrace, M. G., Ghibelli, L., Piredda, L., and Melino, G. (1991). The expression of "tissue" transglutaminase in two human cancer cell lines is related with the programmed cell death (apoptosis). Eur J Cell Biol 54, 246-254.
Pietersen, A. M., van der Eb, M. M., Rademaker, H. J., van den Wollenberg, D. J., Rabelink, M. J., Kuppen, P. J., van Dierendonck, J. H., van Ormondt, H., Masman, D., van de Velde, C. J., et al. (1999). Specific tumor-cell killing with adenovirus vectors containing the apoptin gene. Gene Ther 6, 882-892.
Pirrotta, V. (1997). Chromatin-silencing mechanisms in Drosophila maintain patterns of gene expression. Trends Genet 13, 314-318.
Pirrotta, V. (1998). Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 93, 333-336.
Rao, D. S., Hyun, T. S., Kumar, P. D., Mizukami, I. F., Rubin, M. A., Lucas, P. C., Sanda, M. G., and Ross, T. S. (2002). Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J Clin Invest 110, 351-360.
Rohn, J. L., Zhang, Y. H., Aalbers, R. I., Otto, N., Den Hertog, J., Henriquez, N. V., Van De Velde, C. J., Kuppen, P. J., Mumberg, D., Donner, P., and Noteborn, M. H. (2002). A tumor-specific kinase activity regulates the viral death protein apoptin. J Biol Chem 277, 50820-50827.
Ross, T. S., Bernard, O. A., Berger, R., and Gilliland, D. G. (1998). Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91, 4419-4426.
Rothe, M., Wong, S. C., Henzel, W. J., and Goeddel, D. V. (1994). A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78, 681-692.
Rotonda, J., Nicholson, D. W., Fazil, K. M., Gallant, M., Gareau, Y., Labelle, M., Peterson, E. P., Rasper, D. M., Ruel, R., Vaillancourt, J. P., et al. (1996). The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis. Nat Struct Biol 3, 619-625.
Sanchez, I., Xu, C. J., Juo, P., Kakizaka, A., Blenis, J., and Yuan, J. (1999). Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22, 623-633.
Savill, J., Dransfield, I., Hogg, N., and Haslett, C. (1990). Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343, 170-173.
Srinivasula, S. M., Ahmad, M., Fernandes-Alnemri, T., Litwack, G., and Alnemri, E. S. (1996a). Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc Natl Acad Sci U S A 93, 14486-14491.
Sawa, C., Yoshikawa, T., Matsuda-Suzuki, F., Delehouzee, S., Goto, M., Watanabe, H., Sawada, J., Kataoka, K., and Handa, H. (2002). YEAF1/RYBP and YAF-2 are functionally distinct members of a cofactor family for the YY1 and E4TF1/hGABP transcription factors. J Biol Chem 277, 22484-22490.
Schickling, O., Stegh, A. H., Byrd, J., and Peter, M. E. (2001). Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription. Cell Death Differ 8, 1157-1168.
Schlisio, S., Halperin, T., Vidal, M., and Nevins, J. R. (2002). Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function. Embo J 21, 5775-5786.
Sorensen, S. A., Fenger, K., and Olsen, J. H. (1999). Significantly lower incidence of cancer among patients with Huntington disease: An apoptotic effect of an expanded polyglutamine tract? Cancer 86, 1342-1346.
Srinivasula, S. M., Fernandes-Alnemri, T., Zangrilli, J., Robertson, N., Armstrong, R. C., Wang, L., Trapani, J. A., Tomaselli, K. J., Litwack, G., and Alnemri, E. S. (1996b). The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32. J Biol Chem 271, 27099-27106.
Stacey, N. H., Bishop, C. J., Halliday, J. W., Halliday, W. J., Cooksley, W. G., Powell, L. W., and Kerr, J. F. (1985). Apoptosis as the mode of cell death in antibody-dependent lymphocytotoxicity. J Cell Sci 74, 169-179.
Stanger, B. Z., Leder, P., Lee, T. H., Kim, E., and Seed, B. (1995). RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell 81, 513-523.
Stegh, A. H., Schickling, O., Ehret, A., Scaffidi, C., Peterhansel, C., Hofmann, T. G., Grummt, I., Krammer, P. H., and Peter, M. E. (1998). DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. Embo J 17, 5974-5986.
Steller, H. (1995). Mechanisms and genes of cellular suicide. Science 267, 1445-1449.
Suda, T., Takahashi, T., Golstein, P., and Nagata, S. (1993). Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75, 1169-1178.
Tartaglia, L. A., Ayres, T. M., Wong, G. H., and Goeddel, D. V. (1993). A novel domain within the 55 kd TNF receptor signals cell death. Cell 74, 845-853.
Tewari, M., Quan, L. T., O'Rourke, K., Desnoyers, S., Zeng, Z., Beidler, D. R., Poirier, G. G., Salvesen, G. S., and Dixit, V. M. (1995). Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81, 801-809.
Thomas, L. B., Gates, D. J., Richfield, E. K., O'Brien, T. F., Schweitzer, J. B., and Steindler, D. A. (1995). DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions. Exp Neurol 133, 265-272.
Thornberry, N. A., Bull, H. G., Calaycay, J. R., Chapman, K. T., Howard, A. D., Kostura, M. J., Miller, D. K., Molineaux, S. M., Weidner, J. R., Aunins, J., and et al. (1992). A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356, 768-774.
Ting, A. T., Pimentel-Muinos, F. X., and Seed, B. (1996). RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. Embo J 15, 6189-6196.
Todd, D., Creelan, J. L., Mackie, D. P., Rixon, F., and McNulty, M. S. (1990). Purification and biochemical characterization of chicken anaemia agent. J Gen Virol 71 ( Pt 4), 819-823.
Trimarchi, J. M., Fairchild, B., Wen, J., and Lees, J. A. (2001). The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex. Proc Natl Acad Sci U S A 98, 1519-1524.
Vander Heiden, M. G., Chandel, N. S., Schumacker, P. T., and Thompson, C. B. (1999). Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell 3, 159-167.
Varfolomeev, E. E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J. S., Mett, I. L., Rebrikov, D., Brodianski, V. M., Kemper, O. C., Kollet, O., et al. (1998). Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267-276.
Vaux, D. L., Haecker, G., and Strasser, A. (1994). An evolutionary perspective on apoptosis. Cell 76, 777-779.
Vincenz, C., and Dixit, V. M. (1997). Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. J Biol Chem 272, 6578-6583.
Walker, N. I., and Gobe, G. C. (1987). Cell death and cell proliferation during atrophy of the rat parotid gland induced by duct obstruction. J Pathol 153, 333-344.
Walker, N. P., Talanian, R. V., Brady, K. D., Dang, L. C., Bump, N. J., Ferenz, C. R., Franklin, S., Ghayur, T., Hackett, M. C., Hammill, L. D., and et al. (1994). Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer. Cell 78, 343-352.
Wang, L., Miura, M., Bergeron, L., Zhu, H., and Yuan, J. (1994). Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 78, 739-750.
Wang, X., Johansen, L. M., Tae, H. J., and Taparowsky, E. J. (1996). IFP 35 forms complexes with B-ATF, a member of the AP1 family of transcription factors. Biochem Biophys Res Commun 229, 316-322.
Wanker, E. E., Rovira, C., Scherzinger, E., Hasenbank, R., Walter, S., Tait, D., Colicelli, J., and Lehrach, H. (1997). HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet 6, 487-495.
Wellington, C. L., Brinkman, R. R., O'Kusky, J. R., and Hayden, M. R. (1997). Toward understanding the molecular pathology of Huntington's disease. Brain Pathol 7, 979-1002.
Wellington, C. L., Ellerby, L. M., Gutekunst, C. A., Rogers, D., Warby, S., Graham, R. K., Loubser, O., van Raamsdonk, J., Singaraja, R., Yang, Y. Z., et al. (2002). Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J Neurosci 22, 7862-7872.
Wilson, K. P., Black, J. A., Thomson, J. A., Kim, E. E., Griffith, J. P., Navia, M. A., Murcko, M. A., Chambers, S. P., Aldape, R. A., Raybuck, S. A., and et al. (1994). Structure and mechanism of interleukin-1 beta converting enzyme. Nature 370, 270-275.
Woo, M., Hakem, R., Soengas, M. S., Duncan, G. S., Shahinian, A., Kagi, D., Hakem, A., McCurrach, M., Khoo, W., Kaufman, S. A., et al. (1998). Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 12, 806-819.
Wyllie, A. H., Kerr, J. F., and Currie, A. R. (1980). Cell death: the significance of apoptosis. Int Rev Cytol 68, 251-306.
Young, A. R. (1987). The sunburn cell. Photodermatol 4, 127-134.
Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M., and 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.
Zhang, Y. H., Abrahams, P. J., van der Eb, A. J., and Noteborn, M. H. (1999). The viral protein Apoptin induces apoptosis in UV-C-irradiated cells from individuals with various hereditary cancer-prone syndromes. Cancer Res 59, 3010-3015.
Zheng, L., Schickling, O., Peter, M. E., and Lenardo, M. J. (2001). The death effector domain-associated factor plays distinct regulatory roles in the nucleus and cytoplasm. J Biol Chem 276, 31945-31952.
Zhou, X., Liao, J., Meyerdierks, A., Feng, L., Naumovski, L., Bottger, E. C., and Omary, M. B. (2000). Interferon-alpha induces nmi-IFP35 heterodimeric complex formation that is affected by the phosphorylation of IFP35. J Biol Chem 275, 21364-21371.
Zhuang, S. M., Landegent, J. E., Verschueren, C. A., Falkenburg, J. H., van Ormondt, H., van der Eb, A. J., and Noteborn, M. H. (1995a). Apoptin, a protein encoded by chicken anemia virus, induces cell death in various human hematologic malignant cells in vitro. Leukemia 9 Suppl 1, S118-120.
Zhuang, S. M., Shvarts, A., Jochemsen, A. G., van Oorschot, A. A., van der Eb, A. J., and Noteborn, M. H. (1995b). Differential sensitivity to Ad5 E1B-21kD and Bcl-2 proteins of apoptin-induced versus p53-induced apoptosis. Carcinogenesis 16, 2939-2944.
Zou, H., Henzel, W. J., Liu, X., Lutschg, A., and 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.