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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄧述諄(Shu-Chun Teng) | |
dc.contributor.author | Yu-Chen Chen | en |
dc.contributor.author | 陳育辰 | zh_TW |
dc.date.accessioned | 2021-06-17T07:39:02Z | - |
dc.date.available | 2019-08-27 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-03-05 | |
dc.identifier.citation | 1. Harman D. The aging process. Proc Natl Acad Sci U S A. 1981;78(11):7124-8.
2. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217. 3. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989;5(3):155-71; discussion 72. 4. de Cabo R, Liu L, Ali A, Price N, Zhang J, Wang M, et al. Serum from calorie-restricted animals delays senescence and extends the lifespan of normal human fibroblasts in vitro. Aging (Albany NY). 2015;7(3):152-66. 5. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014;157(7):1515-26. 6. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002;418(6895):344-8. 7. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16(3):129-37. 8. Roth GS, Ingram DK, Lane MA. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001;928:305-15. 9. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289(5487):2126-8. 10. Tesch P, Sjodin B, Thorstensson A, Karlsson J. Muscle fatigue and its relation to lactate accumulation and LDH activity in man. Acta Physiol Scand. 1978;103(4):413-20. 11. Mortimer RK, Johnston JR. Life span of individual yeast cells. Nature. 1959;183(4677):1751-2. 12. Longo VD, Fabrizio P. Chronological aging in Saccharomyces cerevisiae. Subcell Biochem. 2012;57:101-21. 13. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14(10):885-90. 14. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001;292(5515):288-90. 15. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008;4(1):e13. 16. Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010;328(5976):321-6. 17. Orlova M, Kanter E, Krakovich D, Kuchin S. Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae. Eukaryot Cell. 2006;5(11):1831-7. 18. Lin SS, Manchester JK, Gordon JI. Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in Saccharomyces cerevisiae by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem. 2003;278(15):13390-7. 19. Wierman MB, Maqani N, Strickler E, Li M, Smith JS. Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway. Mol Cell Biol. 2017;37(13). 20. Wang Z, Wilson WA, Fujino MA, Roach PJ. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol. 2001;21(17):5742-52. 21. Wright RM, Poyton RO. Release of two Saccharomyces cerevisiae cytochrome genes, COX6 and CYC1, from glucose repression requires the SNF1 and SSN6 gene products. Mol Cell Biol. 1990;10(3):1297-300. 22. Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell. 2007;28(5):739-45. 23. Lee JH, Mand MR, Kao CH, Zhou Y, Ryu SW, Richards AL, et al. ATM directs DNA damage responses and proteostasis via genetically separable pathways. Sci Signal. 2018;11(512). 24. Corcoles-Saez I, Dong K, Johnson AL, Waskiewicz E, Costanzo M, Boone C, et al. Essential Function of Mec1, the Budding Yeast ATM/ATR Checkpoint-Response Kinase, in Protein Homeostasis. Dev Cell. 2018;46(4):495-503 e2. 25. Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18(6):345-60. 26. Mi H, Muruganujan A, Casagrande JT, Thomas PD. Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013;8(8):1551-66. 27. Dilova I, Easlon E, Lin SJ. Calorie restriction and the nutrient sensing signaling pathways. Cell Mol Life Sci. 2007;64(6):752-67. 28. Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 2010;1:e10. 29. Cheong H, Yorimitsu T, Reggiori F, Legakis JE, Wang CW, Klionsky DJ. Atg17 regulates the magnitude of the autophagic response. Mol Biol Cell. 2005;16(7):3438-53. 30. Sia RA, Mitchell AP. Stimulation of later functions of the yeast meiotic protein kinase Ime2p by the IDS2 gene product. Mol Cell Biol. 1995;15(10):5279-87. 31. Neuberger G, Schneider G, Eisenhaber F. pkaPS: prediction of protein kinase A phosphorylation sites with the simplified kinase-substrate binding model. Biol Direct. 2007;2:1. 32. Sharmin D, Sasano Y, Sugiyama M, Harashima S. Effects of deletion of different PP2C protein phosphatase genes on stress responses in Saccharomyces cerevisiae. Yeast. 2014;31(10):393-409. 33. Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, et al. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. Front Neurosci. 2017;11:254. 34. Liu PJ, Chen CD, Wang CL, Wu YC, Hsu CW, Lee CW, et al. In-depth proteomic analysis of six types of exudative pleural effusions for nonsmall cell lung cancer biomarker discovery. Molecular & cellular proteomics : MCP. 2015;14(4):917-32. 35. Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta. 2012;1823(3):624-35. 36. Richter K, Walter S, Buchner J. The Co-chaperone Sba1 connects the ATPase reaction of Hsp90 to the progression of the chaperone cycle. J Mol Biol. 2004;342(5):1403-13. 37. Wolmarans A, Lee B, Spyracopoulos L, LaPointe P. The Mechanism of Hsp90 ATPase Stimulation by Aha1. Sci Rep. 2016;6:33179. 38. Francis BR, Thorsness PE. Hsp90 and mitochondrial proteases Yme1 and Yta10/12 participate in ATP synthase assembly in Saccharomyces cerevisiae. Mitochondrion. 2011;11(4):587-600. 39. Wang Y, Singh U, Mueller DM. Mitochondrial genome integrity mutations uncouple the yeast Saccharomyces cerevisiae ATP synthase. J Biol Chem. 2007;282(11):8228-36. 40. Distel B, Gould, SJ., Voorn-Brouwer, T., van der Berg, M., Tabak, HF., Subramani, S. The carboxyl-terminal tripeptide serine-lysine-leucine of firefly luciferase is necessary but not sufficient for peroxisomal import in yeast. New Biol. 1992;4(2):157-65. 41. Schena M, Yamamoto KR. Mammalian glucocorticoid receptor derivatives enhance transcription in yeast. Science. 1988;241(4868):965-7. 42. Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, et al. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell. 2012;150(5):987-1001. 43. Nathan DF, Lindquist S. Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol Cell Biol. 1995;15(7):3917-25. 44. Chiti F, Dobson CM. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu Rev Biochem. 2017;86:27-68. 45. O'Connell JD, Tsechansky M, Royal A, Boutz DR, Ellington AD, Marcotte EM. A proteomic survey of widespread protein aggregation in yeast. Mol Biosyst. 2014;10(4):851-61. 46. Hsieh YY, Hung PH, Leu JY. Hsp90 regulates nongenetic variation in response to environmental stress. Mol Cell. 2013;50(1):82-92. 47. Franzosa EA, Albanese V, Frydman J, Xia Y, McClellan AJ. Heterozygous yeast deletion collection screens reveal essential targets of Hsp90. PLoS One. 2011;6(11):e28211. 48. Kravats AN, Hoskins JR, Reidy M, Johnson JL, Doyle SM, Genest O, et al. Functional and physical interaction between yeast Hsp90 and Hsp70. Proc Natl Acad Sci U S A. 2018;115(10):E2210-E9. 49. Yang X, Zhang Y, Xu W, Deng R, Liu Y, Li F, et al. Potential role of Hsp90 in rat islet function under the condition of high glucose. Acta Diabetol. 2016;53(4):621-8. 50. Lei H, Venkatakrishnan A, Yu S, Kazlauskas A. Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes. J Biol Chem. 2007;282(13):9364-71. 51. Verna J, Lodder A, Lee K, Vagts A, Ballester R. A family of genes required for maintenance of cell wall integrity and for the stress response in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1997;94(25):13804-9. 52. Petkova MI, Pujol-Carrion N, Arroyo J, Garcia-Cantalejo J, Angeles de la Torre-Ruiz M. Mtl1 is required to activate general stress response through Tor1 and Ras2 inhibition under conditions of glucose starvation and oxidative stress. J Biol Chem. 2010;285(25):19521-31. 53. Arino J, Casamayor A, Gonzalez A. Type 2C protein phosphatases in fungi. Eukaryot Cell. 2011;10(1):21-33. 54. Warmka J, Hanneman J, Lee J, Amin D, Ota I. Ptc1, a type 2C Ser/Thr phosphatase, inactivates the HOG pathway by dephosphorylating the mitogen-activated protein kinase Hog1. Mol Cell Biol. 2001;21(1):51-60. 55. Aluru M, McKinney T, Venero AL, Choudhury S, Torres M. Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast. Aging (Albany NY). 2017;9(12):2587-609. 56. Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature. 2006;440(7087):1013-7. 57. Rohl A, Rohrberg J, Buchner J. The chaperone Hsp90: changing partners for demanding clients. Trends Biochem Sci. 2013;38(5):253-62. 58. Meyer P, Prodromou C, Liao C, Hu B, Roe SM, Vaughan CK, et al. Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J. 2004;23(6):1402-10. 59. Wang YT, Tsai CF, Hong TC, Tsou CC, Lin PY, Pan SH, et al. An informatics-assisted label-free quantitation strategy that depicts phosphoproteomic profiles in lung cancer cell invasion. Journal of proteome research. 2010;9(11):5582-97. 60. Kanehisa M, and Susumu Goto. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. 2000;28(1):27-30. 61. Portela P, Howell S, Moreno S, Rossi S. In vivo and in vitro phosphorylation of two isoforms of yeast pyruvate kinase by protein kinase A. J Biol Chem. 2002;277(34):30477-87. 62. Roskoski R. Assays of protein kinase. Methods in Enzymology. 1983;99:3-6. 63. Vizcaino JA, Deutsch EW, Wang R, Csordas A, Reisinger F, Rios D, et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat Biotechnol. 2014;32(3):223-6. 64. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature genetics. 2000;25(1):25-49. 65. Dennis G Jr1 SB, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003;4(5):3. 66. Postnikoff SD, Harkness TA. Replicative and chronological life-span assays. Methods Mol Biol. 2014;1163:223-7. 67. Longo VD, Shadel GS, Kaeberlein M, Kennedy B. Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab. 2012;16(1):18-31. 68. Smith DL, Jr., McClure JM, Matecic M, Smith JS. Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. Aging Cell. 2007;6(5):649-62. 69. Tsai CF, Wang YT, Chen YR, Lai CY, Lin PY, Pan KT, et al. Immobilized metal affinity chromatography revisited: pH/acid control toward high selectivity in phosphoproteomics. Journal of proteome research. 2008;7(9):4058-69. 70. Toone WM, Jones N. Stress-activated signalling pathways in yeast. Genes to cells : devoted to molecular & cellular mechanisms. 1998;3(8):485-98. 71. Zuehlke AD, Reidy M, Lin C, LaPointe P, Alsomairy S, Lee DJ, et al. An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans. Nat Commun. 2017;8:15328. 72. Boczek EE, Reefschlager LG, Dehling M, Struller TJ, Hausler E, Seidl A, et al. Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90. Proc Natl Acad Sci U S A. 2015;112(25):E3189-98. 73. Sievers F, Higgins DG. Clustal omega. Curr Protoc Bioinformatics. 2014;48:3 13 1-6. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73509 | - |
dc.description.abstract | 老化是與生理功能逐漸喪失所造成相關的複雜現象,其中與老化相關的因子包括營養物質的感受與蛋白質穩定都會控制壽命的長短。雖然目前研究有許多方法鑑定控制長壽的候選基因,但是參與老化途徑的分子機制仍需要更深入的研究。在本研究中,我們使用了質譜儀定量分析技術進行篩選,並鑑定了酵母蛋白中受到卡路里限制時具有顯著改變的磷酸化/去磷酸化位點。針對其中135個蛋白進行功能性分析,發現Ids2在卡路里限制下會被PP2C去磷酸化並且活化,而相反的,在糖類過多的狀態下會被PKA而抑制其活性。在ids2以及模擬磷酸化ids2的細胞經測試顯示對熱的感受性增加以及壽命縮短。此外,Ids2可能作為HSP90 (Hsc82, Hsp82)的分子伴侶(co-chaperone)蛋白,會與之結合並形成複合物來增強蛋白摺疊活性,然而經磷酸化的Ids2會阻礙其與HSP90的結合。因此,細胞可藉由PP2C和PKA途徑因應糖類的多寡來調控蛋白質摺疊活性,使細胞能夠維持蛋白質的品質以及維持細胞的壽命。
在另一個與老化相關的層面,ATM與ATR在之前被認為是DNA受損關鍵性調控的激酶,然而在近期發現可能會影響造成蛋白質摺疊。所以在本研究中,我們測試ATM與ATR是否會藉由HSP90複合蛋白的調控機制來影響蛋白質的品質。結果顯示ATM與ATR的確會影響HSP90的活性,但詳細機制仍需更進一步的研究。 | zh_TW |
dc.description.abstract | Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.
At another level associated with aging, ATM and ATR were previously thought to be key regulators of DNA damage but recently found to have an additional role in protein folding. We therefore tested whether ATM and ATR survey the quality of proteins via the regulatory mechanism of HSP90 chaperone complex. The results showed that ATM and ATR affect the activity of HSP90, but the detailed mechanism remains further study. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T07:39:02Z (GMT). No. of bitstreams: 1 ntu-108-D96445007-1.pdf: 4139619 bytes, checksum: c00918196f6b730561ca105969701d8f (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii 中文摘要 iii Abstract iv Introduction 1 Results 4 Discussion 14 Methods 18 Figures and Figure Legends 34 References 71 Appendix figures 82 | |
dc.language.iso | en | |
dc.title | 過多糖類攝取會經由PKA調控來降低HSP90蛋白質摺疊活性 | zh_TW |
dc.title | Glucose intake hampers PKA-regulated HSP90 chaperone activity | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 冀宏源,吳青錫,林敬哲,劉雅雯 | |
dc.subject.keyword | 蛋白質摺疊,蛋白質衡定,卡路里限制,分子伴侶蛋白, | zh_TW |
dc.subject.keyword | HSP90,calorie restriction,PKA,PP2C,proteostasis, | en |
dc.relation.page | 85 | |
dc.identifier.doi | 10.6342/NTU201900634 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-03-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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