進階搜尋


下載電子全文  
系統識別號 U0026-2307201214002000
論文名稱(中文) 泛素特異性胜酶24對組蛋白的影響
論文名稱(英文) The Effect of Ubiquitin Specific Peptidase 24 on Histones
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 100
學期 2
出版年 101
研究生(中文) 莊縕沛
研究生(英文) Yun-Pei Chuang
學號 s26994087
學位類別 碩士
語文別 英文
論文頁數 70頁
口試委員 口試委員-呂增宏
指導教授-洪建中
共同指導教授-張文昌
中文關鍵字 組蛋白  基因穩定性  泛素特異性胜肽酶 24 
英文關鍵字 histones  genome stability  USP 24 
學科別分類
中文摘要 真核細胞的DNA由核心組蛋白 (core histones) 及連結組蛋白 (linker histone) 纏繞而成核小體 (nucleosomes)。組蛋白之N端尾 (N-terminal tail) 的轉譯後修飾 (posttranslational modifications, PTMs) 如甲基化 (methylation)、乙醯化 (acetylation)、磷酸化 (phosphorylation) 以及泛素化 (ubiquitination) 所形成之組蛋白碼 (histone code) 可進一步調控細胞的基因轉錄作用 (gene transcription),進而影響 DNA 修復、重組、複製以及染色質結構。在將 DNA 包裹成染色質 (chromatin) 時,細胞必須嚴謹地維持組蛋白和 DNA 合成之間的平衡。目前已有研究指出,過多的組蛋白堆積會造成染色質缺失並增加細胞對 DNA 損害及細胞毒性的敏感度,由此可知,組蛋白表現對於維持基因穩定性是非常重要的。但是,如何維持組蛋白的穩定表現仍然是未知的。在此項研究中,我們發現一種去泛素化蛋白 ─ 泛素特異性胜肽酶 24 (ubiquitin specific peptidase 24, USP24) 能夠調控組蛋白表現。在人類肺腺癌細胞株 A549 中靜默 (knockdown) USP24 表現後,大部分的組蛋白包括 H1、H2A、H2B 和 H4 表現量都有顯著增加。此外,經由細胞計數 (cell counting) 和細胞存活率分析 (MTT assay) 得知,靜默 USP24 表現顯著增強細胞增生和存活率。相較於蛋白質表現量, USP24 對於組蛋白 mRNA 所造成的影響較為有限,因此,為了進一步提出 USP24 是透過何種機制影響組蛋白表現,我們接著分析蛋白質穩定性,結果發現在抑制 USP24 之後,細胞中的組蛋白質穩定性有顯著上升,因此證明 USP24 是透過維持組蛋白的穩定而調節其表現。反之,從免疫螢光染色 (immunofluorescence assay) 結果得知,在過度表現 USP24 的細胞中,組蛋白表現訊號明顯減弱,最終促使細胞走向死亡。最後,根據免疫螢光染色結果,我們大膽推測 USP24 可能與細胞核中的泛素蛋白酶體系統 (nucleus ubiquitin proteasome system, nUPS) 存在共位現象 (colocalization),暗示了 USP24 也許在細胞核中負責進行蛋白質的降解作用。總結此項研究結果,我們證實 USP24 能夠調控組蛋白表現並進而提高細胞的存活率且維持基因組的穩定性。
英文摘要 Core histones involves in DNA packaging hence regulate gene expression in interphase and divide genome into daughter cells in mitosis. The variety of post-translational modifications, including acetylation, phosphorylation, methylation and ubiquitination, play important roles in the epigenetic control of gene expression. However, how to maintain histones level has yet to be addressed. In this study, we found that a deubiquitin protein, ubiquitin specific peptidase 24 (USP24) could affect histone level. Under transient knock-down of USP24 in A549 cells, most histones including H1, H2A, H2B and H4 were increased dramatically, leading an increase in cell number and viability. To further address the mechanism of how USP24 affect the histone level, only little contribution from modulating the mRNA level of histones by USP24. The stability of most histones was increased significantly, indicating that the increase in histones level under silence of USP24 was due to the enhancement of histones protein stability. On the other hand, as GFP-USP24 was overexpressed inside A549 cells, the signal of histones was decreased and chromatin was looser, finally resulting in cell death. Furthermore, localization study found that USP24 stayed mainly in cytoplasm, but some of which still in nucleus. Our recent preliminary results in Immunofluorescence assay indicated that USP24 might colocalized with nucleus ubiquitin proteasome system (nUPS), suggesting that it might work with nUPS to perform the protein degradation inside nucleus. Therefore, unraveling the detailed mechanism of how USP24 affect the stability of histones is ongoing in our laboratory. In conclusion, it is important to clarify the role of USP24 in protein degradation and might be advantage to the study of abnormal protein aggregation such as Parkinson’s disease and tumorignensis.
論文目次 Abstract in Chinese I
Abstract III
Acknowledgement V
Contents VII
Figure contents XI
Appendix contents XII
Abbreviation list XIII
Introduction 1
Ⅰ. Histones 1
1. The overview of histones 1
2. The posttranslational modifications (PTMs) of histones 1
2.1 Histone acetylation 2
2.2 Histone phosphorylation 3
2.3 Histone ubiquitination 3
2.4 Histone methylation 4
Ⅱ. Posttranslational modifications of histone and transcriptional regulation 5
Ⅲ. Alterations of histone protein levels in cells and their importance in genomic stability 6
Ⅳ. Ubiquitin specific peptidase (USP) 24 7
1. Deubiquitination 7
2. The structure of USPs 7
3. The function of USPs 8
4. USPs and histone modifications 9
5. USP24 10
Ⅴ. Research aims 10
Materials and methods 12
Ⅰ. Materials 12
Ⅱ. Methods 19
1. Cell culture 19
2. Production and infection of recombinant lentiviral particles 19
3. Western blot analysis 19
4. Isolation of plasmid DNA 20
5. Transient transfection assay 21
6. Reverse transcription-polymerase chain reaction (RT-PCR) 21
7. Polymerase chain reaction (PCR) 22
8. Agarose DNA gel electrophoresis 22
9. MTS cell viability assay 22
10. Fluorescence-activated cell sorting (FACS) analysis 23
11. Subcellular fractionation 23
12. Plasmid construction of GFP-USP24 24
12.1 Construction of yT&A-USP24 plasmids 24
12.2 Transformation of yT&A-USP24 plasmids 25
12.3 Restriction digestion and ligation of yT&A-USP24 plasmids 25
13. Immunoflourescence 26
14. Statistical analysis 26
Results 27
1. Posttranslational modifications of histones are modulated by USP24 27
2. mRNA level of histones is not affected significantly but histone protein levels are principally regulated by USP24 27
3. Overexpression of GFP-USP24 down-regulates histone H1 and H2A protein expression levels 28
4. The increase in histones level under silence of USP24 is due to the enhancement of histones protein stability 29
5. Most histone protein stability and expression levels are up-regulated and consequently cell number and viability are enhanced under silence of USP24 30
6. USP24 inhibits A549 cell proliferation by delaying G1/S phase transition in cell cycle 30
7. Conclusion 31
Discussion 32
References 58
Curriculum vitae 70
Figure 1. The effect of USPs on histone H2B monoubiquitination. 37
Figure 2. Expression levels of posttranslational histone modifications. 38
Figure 3. Protein levels of histones. 40
Figure 4. mRNA levels of total histones. 45
Figure 5. Immunofluorescence images of Histone H1 and H2A.x in USP24 overexpressing cells. 43
Figure 6. Transportation of histone H2B mRNA in A549 cells. 47
Figure 7. Half-life of histones under silence of USP24. 48
Figure 8. Evaluation of cell numbers and viability. 52
Figure 9. Identificaion of USP24-regulated gene expression related to G2/M phase in cell cycle. 54
Figure 10. Flow cytometry analysis. 56
Figure 11. Working model. 57
Appendix 1. Posttranslational modifications of human nucleosomal histones. 67
Appendix 2. The molecular machinery required for histone H3 methylation on lysines 4 and 79 68
Appendix 3. Schematic representation of the ubiquitin-proteasome system with different effectors 69
參考文獻 Ahn, S. H., Henderson, K. A., Keeney, S., and Allis, C. D. (2005). H2B (Ser10) phosphorylation is induced during apoptosis and meiosis in S. cerevisiae. Cell Cycle 4, 780-783.
Avvakumov, G. V., Walker, J. R., Xue, S., Finerty, P. J., Jr., Mackenzie, F., Newman, E. M., and Dhe-Paganon, S. (2006). Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). J Biol Chem 281, 38061-38070.
Baek, K. H. (2003). Conjugation and deconjugation of ubiquitin regulating the destiny of proteins. Exp Mol Med 35, 1-7.
Barber, C. M., Turner, F. B., Wang, Y., Hagstrom, K., Taverna, S. D., Mollah, S., Ueberheide, B., Meyer, B. J., Hunt, D. F., Cheung, P., and Allis, C. D. (2004). The enhancement of histone H4 and H2A serine 1 phosphorylation during mitosis and S-phase is evolutionarily conserved. Chromosoma 112, 360-371.
Bhaumik, S. R., Smith, E., and Shilatifard, A. (2007). Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14, 1008-1016.
Borodovsky, A., Ovaa, H., Kolli, N., Gan-Erdene, T., Wilkinson, K. D., Ploegh, H. L., and Kessler, B. M. (2002). Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol 9, 1149-1159.
Bradbury, E. M. (1992). Reversible histone modifications and the chromosome cell cycle. Bioessays 14, 9-16.
Brichory, F., Beer, D., Le Naour, F., Giordano, T., and Hanash, S. (2001). Proteomics-based identification of protein gene product 9.5 as a tumor antigen that induces a humoral immune response in lung cancer. Cancer Res 61, 7908-7912.
Brummelkamp, T. R., Nijman, S. M., Dirac, A. M., and Bernards, R. (2003). Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424, 797-801.
Daviet, L., and Colland, F. (2008). Targeting ubiquitin specific proteases for drug discovery. Biochimie 90, 270-283.
Du, Y., Xu, N., Lu, M., and Li, T. (2011). hUbiquitome: a database of experimentally verified ubiquitination cascades in humans. Database (Oxford) 2011, bar055.
Ehrenhofer-Murray, A. E. (2004). Chromatin dynamics at DNA replication, transcription and repair. Eur J Biochem 271, 2335-2349.
Feng, Q., Wang, H., Ng, H. H., Erdjument-Bromage, H., Tempst, P., Struhl, K., and Zhang, Y. (2002). Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12, 1052-1058.
Foster, E. R., and Downs, J. A. (2005). Histone H2A phosphorylation in DNA double-strand break repair. FEBS J 272, 3231-3240.
Gavioli, R., Frisan, T., Vertuani, S., Bornkamm, G. W., and Masucci, M. G. (2001). c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol 3, 283-288.
Gilchrist, C. A., and Baker, R. T. (2000). Characterization of the ubiquitin-specific protease activity of the mouse/human Unp/Unph oncoprotein. Biochim Biophys Acta 1481, 297-309.
Glickman, M. H., and Ciechanover, A. (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82, 373-428.
Gray, D. A., Inazawa, J., Gupta, K., Wong, A., Ueda, R., and Takahashi, T. (1995). Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung tumors. Oncogene 10, 2179-2183.
Groth, A., Rocha, W., Verreault, A., and Almouzni, G. (2007). Chromatin challenges during DNA replication and repair. Cell 128, 721-733.
Gunjan, A., and Verreault, A. (2003). A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell 115, 537-549.
Han, M., Chang, M., Kim, U. J., and Grunstein, M. (1987). Histone H2B repression causes cell-cycle-specific arrest in yeast: effects on chromosomal segregation, replication, and transcription. Cell 48, 589-597.
Henry, K. W., Wyce, A., Lo, W. S., Duggan, L. J., Emre, N. C., Kao, C. F., Pillus, L., Shilatifard, A., Osley, M. A., and Berger, S. L. (2003). Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev 17, 2648-2663.
Hu, M., Li, P., Li, M., Li, W., Yao, T., Wu, J. W., Gu, W., Cohen, R. E., and Shi, Y. (2002). Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111, 1041-1054.
Hu, M., Li, P., Song, L., Jeffrey, P. D., Chenova, T. A., Wilkinson, K. D., Cohen, R. E., and Shi, Y. (2005). Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J 24, 3747-3756.
Huang, S., Litt, M., and Felsenfeld, G. (2005). Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications. Genes Dev 19, 1885-1893.
Huyen, Y., Zgheib, O., Ditullio, R. A., Jr., Gorgoulis, V. G., Zacharatos, P., Petty, T. J., Sheston, E. A., Mellert, H. S., Stavridi, E. S., and Halazonetis, T. D. (2004). Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406-411.
Janssen, J. W., Schleithoff, L., Bartram, C. R., and Schulz, A. S. (1998). An oncogenic fusion product of the phosphatidylinositol 3-kinase p85beta subunit and HUMORF8, a putative deubiquitinating enzyme. Oncogene 16, 1767-1772.
Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., et al. (1998). BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097-1112.
Keogh, M. C., Kurdistani, S. K., Morris, S. A., Ahn, S. H., Podolny, V., Collins, S. R., Schuldiner, M., Chin, K., Punna, T., Thompson, N. J., et al. (2005). Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593-605.
Klose, R. J., and Zhang, Y. (2007). Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8, 307-318.
Komander, D., Lord, C. J., Scheel, H., Swift, S., Hofmann, K., Ashworth, A., and Barford, D. (2008). The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 29, 451-464.
Kornberg, R. D. (1974). Chromatin structure: a repeating unit of histones and DNA. Science 184, 868-871.
Kornberg, R. D., and Lorch, Y. (1999). Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285-294.
Koshland, D., and Strunnikov, A. (1996). Mitotic chromosome condensation. Annu Rev Cell Dev Biol 12, 305-333.
Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705.
Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israel, A., Wallach, D., and Courtois, G. (2003). The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424, 801-805.
Kusch, T., and Workman, J. L. (2007). Histone variants and complexes involved in their exchange. Subcell Biochem 41, 91-109.
Lacoste, N., Utley, R. T., Hunter, J. M., Poirier, G. G., and Cote, J. (2002). Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase. J Biol Chem 277, 30421-30424.
Lanctot, C., Cheutin, T., Cremer, M., Cavalli, G., and Cremer, T. (2007). Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat Rev Genet 8, 104-115.
Lee, D. Y., Teyssier, C., Strahl, B. D., and Stallcup, M. R. (2005). Role of protein methylation in regulation of transcription. Endocr Rev 26, 147-170.
Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1998). Genetic instabilities in human cancers. Nature 396, 643-649.
Li, B., Carey, M., and Workman, J. L. (2007). The role of chromatin during transcription. Cell 128, 707-719.
Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J., and Gu, W. (2002a). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653.
Li, Y., Schrodi, S., Rowland, C., Tacey, K., Catanese, J., and Grupe, A. (2006). Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease. Hum Mutat 27, 1017-1023.
Li, Z., Wang, D., Na, X., Schoen, S. R., Messing, E. M., and Wu, G. (2002b). Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor. Biochem Biophys Res Commun 294, 700-709.
Meeks-Wagner, D., and Hartwell, L. H. (1986). Normal stoichiometry of histone dimer sets is necessary for high fidelity of mitotic chromosome transmission. Cell 44, 43-52.
Naviglio, S., Mattecucci, C., Matoskova, B., Nagase, T., Nomura, N., Di Fiore, P. P., and Draetta, G. F. (1998). UBPY: a growth-regulated human ubiquitin isopeptidase. EMBO J 17, 3241-3250.
Ng, H. H., Feng, Q., Wang, H., Erdjument-Bromage, H., Tempst, P., Zhang, Y., and Struhl, K. (2002). Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev 16, 1518-1527.
Nijman, S. M., Luna-Vargas, M. P., Velds, A., Brummelkamp, T. R., Dirac, A. M., Sixma, T. K., and Bernards, R. (2005). A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773-786.
Nowak, S. J., and Corces, V. G. (2004). Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet 20, 214-220.
Prado, F., and Aguilera, A. (2005). Partial depletion of histone H4 increases homologous recombination-mediated genetic instability. Mol Cell Biol 25, 1526-1536.
Pavri, R., Zhu, B., Li, G., Trojer, P., Mandal, S., Shilatifard, A., and Reinberg, D. (2006). Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125, 703-717.
Renatus, M., Parrado, S. G., D'Arcy, A., Eidhoff, U., Gerhartz, B., Hassiepen, U., Pierrat, B., Riedl, R., Vinzenz, D., Worpenberg, S., and Kroemer, M. (2006). Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 14, 1293-1302.
Rice, J. C., Briggs, S. D., Ueberheide, B., Barber, C. M., Shabanowitz, J., Hunt, D. F., Shinkai, Y., and Allis, C. D. (2003). Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 12, 1591-1598.
Ruthenburg, A. J., Li, H., Patel, D. J., and Allis, C. D. (2007). Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8, 983-994.
Sasaki, H., Yukiue, H., Moriyama, S., Kobayashi, Y., Nakashima, Y., Kaji, M., Fukai, I., Kiriyama, M., Yamakawa, Y., and Fujii, Y. (2001). Expression of the protein gene product 9.5, PGP9.5, is correlated with T-status in non-small cell lung cancer. Jpn J Clin Oncol 31, 532-535.
Schneider, J., and Shilatifard, A. (2006). Histone demethylation by hydroxylation: chemistry in action. ACS Chem Biol 1, 75-81.
Schumacher, U., Mitchell, B. S., and Kaiserling, E. (1994). The neuronal marker protein gene product 9.5 (PGP 9.5) is phenotypically expressed in human breast epithelium, in milk, and in benign and malignant breast tumors. DNA Cell Biol 13, 839-843.
Shahbazian, M. D., and Grunstein, M. (2007). Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 76, 75-100.
Shi, Y. (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8, 829-833.
Shilatifard, A. (2006). Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75, 243-269.
Sims, R. J., 3rd, and Reinberg, D. (2006). Histone H3 Lys 4 methylation: caught in a bind? Genes Dev 20, 2779-2786.
Sonoda, E., Sasaki, M. S., Buerstedde, J. M., Bezzubova, O., Shinohara, A., Ogawa, H., Takata, M., Yamaguchi-Iwai, Y., and Takeda, S. (1998). Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J 17, 598-608.
Sonoda, E., Takata, M., Yamashita, Y. M., Morrison, C., and Takeda, S. (2001). Homologous DNA recombination in vertebrate cells. Proc Natl Acad Sci U S A 98, 8388-8394.
Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D., and Patel, D. J. (2007). How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14, 1025-1040.
Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., and Mosialos, G. (2003). CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424, 793-796.
van Leeuwen, F., Gafken, P. R., and Gottschling, D. E. (2002). Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745-756.
Wilkinson, K. D. (1997). Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J 11, 1245-1256.
Woodcock, C. L. (2006). Chromatin architecture. Curr Opin Struct Biol 16, 213-220.
Woodcock, C. L., Skoultchi, A. I., and Fan, Y. (2006). Role of linker histone in chromatin structure and function: H1 stoichiometry and nucleosome repeat length. Chromosome Res 14, 17-25.
Wu, Y. R., Chen, C. M., Chen, Y. C., Chao, C. Y., Ro, L. S., Fung, H. C., Hsiao, Y. C., Hu, F. J., and Lee-Chen, G. J. (2010). Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese. Clin Chim Acta 411, 955-958.
Wyrick, J. J., Holstege, F. C., Jennings, E. G., Causton, H. C., Shore, D., Grunstein, M., Lander, E. S., and Young, R. A. (1999). Chromosomal landscape of nucleosome-dependent gene expression and silencing in yeast. Nature 402, 418-421.
Wysocki, R., Javaheri, A., Allard, S., Sha, F., Cote, J., and Kron, S. J. (2005). Role of Dot1-dependent histone H3 methylation in G1 and S phase DNA damage checkpoint functions of Rad9. Mol Cell Biol 25, 8430-8443.
Zhang, Y. (2003). Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev 17, 2733-2740.
Zhu, Y., Lambert, K., Corless, C., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., and D'Andrea, A. D. (1997). DUB-2 is a member of a novel family of cytokine-inducible deubiquitinating enzymes. J Biol Chem 272, 51-57.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2015-08-06起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2015-08-06起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw