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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Shang-Min Chou | en |
| dc.contributor.author | 周尚民 | zh_TW |
| dc.date.accessioned | 2021-05-20T21:18:34Z | - |
| dc.date.available | 2013-03-03 | |
| dc.date.available | 2021-05-20T21:18:34Z | - |
| dc.date.copyright | 2011-03-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-01-07 | |
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(2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences, Physiol Rev 86, 369-408. 157. Rizzuto, R., Pinton, P., Ferrari, D., Chami, M., Szabadkai, G., Magalhaes, P. J., Di Virgilio, F., and Pozzan, T. (2003) Calcium and apoptosis: facts and hypotheses, Oncogene 22, 8619-8627. 158. Saidak, Z., Mentaverri, R., and Brown, E. M. (2009) The role of the calcium-sensing receptor in the development and progression of cancer, Endocr Rev 30, 178-195. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10304 | - |
| dc.description.abstract | 時間與空間上的嚴格控制對鈣蛋白酶來調控它的蛋白質水解活性功能是很重要的。這裡，我們證實位於細胞質中的鈣蛋白酶2可以切割水解位於細胞核的人類拓樸異構酶1（hTOP1）及拓樸異構酶2 beta (hTOP2 beta)，而拓樸異構酶2 alpha (hTOP2 alpha)並不會被水解切割,此現象可能透過Ca2+所誘導的鈣蛋白酶2進入細胞核而發生。此由以下的證據支持：(一)細胞處理Ca2+或Ca2+離子載體(ionophores)會造成在細胞核內的hTOP1及hTOP2 beta蛋白質被快速切割水解。 （二）兩種Ca2+螯合物都能有效地阻止ionomycin (一種Ca2 +離子載體)所引起的hTOP1及hTOP2 beta的蛋白質切割；而且添加Ca2+可以直接活化細胞萃取物中蛋白酶切割hTOP1與hTOP2 beta的現象；都支持細胞內的鈣離子濃度[Ca2 +]i對於hTOP1與hTOP2 beta蛋白質的切割是必要的。（三）進一步，我們利用重組蛋白質，實驗顯示鈣蛋白酶2 比鈣蛋白酶 1具有更高的效率去切割hTOP1蛋白質。(四)與以上概念一致，我們推論鈣蛋白酶2可能是主要Ca2 +活化切割hTOP1的蛋白酶之一，因為在降低鈣蛋白酶2表現(si-Capn2)的細胞中hTOP1對於ionomycin 誘導的蛋白質切割有高的抗性。(五)另外，我們的實驗也發現hTOP2 beta與hTOP1均是鈣蛋白酶2的新受質，且hTOP2 beta似乎較hTOP1更容易在相同濃度的ionomycin處理下被切割。(六)鈣蛋白酶2所切割hTOP1蛋白質的位置位於hTOP1的N端(N-terminus)第158及183個胺基酸賴胺酸(K158 and K183)上，而切割後的大片斷hTOP1(hTOP1tr)蛋白質則具有更強解螺旋 (relaxation)的能力。（七）此外，hTOP1tr蛋白質依然保有可以和DNA及喜樹鹼(camptothesin，CPT)形成可切割複合體（TOP1 cleavable complex，TOP1cc），並具有與核仁蛋白質nucleolin的蛋白交互作用能力。（八）細胞處理ionomycin後，鈣蛋白酶 2的活化似乎可以保護細胞免於CPT所引起的細胞毒殺害作用。總結,我們的結果為細胞質中的鈣蛋白酶2如何切割細胞核內蛋白質提供了良好的說明與實驗證據支持：在被Ca2+活化後的鈣蛋白酶2會藉由細胞質-核穿梭運輸，讓鈣蛋白酶 2 從細胞質到細胞核從而接觸到並切割其核內受質。 | zh_TW |
| dc.description.abstract | Crucial to calpain function is the tight regulation of its proteolytic activity, which is temporally and spatially controlled. Here, we demonstrated that the cytoplasm-located calpain 2 cleaves human nuclear topoisomerases I (hTOP1) and II beta (hTOP2 beta) but not II alpha (hTOP2 alpha) possibly through the Ca2+-induced nuclear translocation of active proteases. This is supported by the followings: (I) Treatments of cells with Ca2+ or Ca2+ ionophores caused a rapid proteolytic cleavage of hTOP1 and 2 beta in the nucleus. (II) Elevated intracelluar [Ca2+] is responsible for this hTOP1 and 2 beta proteolysis event as suggested by the observations that two Ca2+ chelators could both effectively block the ionomycin-induced cleavage of hTOP1 and 2 beta and addition of Ca2+ in the in vitro protease activation assay caused hTOP1 and 2 beta proteolysis. (III) Using recombinant proteins, our in vitro experiments showed that calpain 2 cleaved hTOP1 more efficient than calpain 1 did.(IV) Consistent with above notion that calpain 2 as a main protease responsible for Ca2+-activated proteolysis of hTOP1, hTOP1 proteins in calpain 2-knockdown (si-Capn2) cells were resistant to the ionomycin-induced proteolysis. (V) Similar to hTOP1, hTOP2 beta has also been identified as a novel substrate for calpain 2. In addition, Ca2+-activated calpain 2 appeared to cleave hTOP2 beta more completed than hTOP1 in the same dose of ionomycin treatment. (VI) The calpain 2 cleavage sites of hTOP1 were mapped at its N’-terminus K158 and K183 and the resulting hTOP1tr exhibited an enhanced relaxation activity. (VII) In addition, the hTOP1tr proteins remained the abilities to form the hTOP1-DNA-camptothecin (CPT) cleavable complex (hTOP1cc) and to interact with nucleolin proteins. (VIII) Ionomycin treatment caused a calpain 2-dependent protection of cells from cytotoxic killing by CPT. In sum, our results provided a good support for the regulation of calpain in the proteolytic cleavage of nuclear proteins via a cytoplasmic-to-nuclear trafficking of calpain 2. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T21:18:34Z (GMT). No. of bitstreams: 1 ntu-100-F90445117-1.pdf: 3615561 bytes, checksum: 185b418eb46a994d7b724c174cf16265 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 中文摘要------------------------------------------------------------------------------------------ I
Abstract------------------------------------------------------------------------------------------ II Abbreviations----------------------------------------------------------------------------------IV Chapter 1. Preface-----------------------------------------------------------------------------1 1.1 DNA topoisomerase family--------------------------------------------------------------1 1.2 The important of DNA topoisomerases in antibiotics and anti-cancer therapy------------------------------------------------------------------------------------------3 1.3 Topoisomerase 1 (eukaryotic)-----------------------------------------------------------4 1.4 Topoisomerase 2 (eukaryotic)-----------------------------------------------------------5 1.5 Topoisomerase 3 (eukaryotic)-----------------------------------------------------------6 1.6 Calpains-------------------------------------------------------------------------------------7 1.7 Functions of calpains---------------------------------------------------------------------9 1.8 Rationale-----------------------------------------------------------------------------------11 Chapter 2. Calcium-induced cleavage of DNA topoisomerase I involving the cytoplasmic-nuclear shuttling of calpain 2----------------------------------------------12 2.1 Introduction-------------------------------------------------------------------------------12 2. 2 Materials and methods-----------------------------------------------------------------16 2.2.1 Drugs, chemicals, reagents and cell cultures--------------------------------------16 2.2.2 Antibodies, immunoblotting and immunofluorescence (IFA)------------------16 2.2.3 In vitro protease activation assay---------------------------------------------------18 2.2.4 Nuclei isolation and cellular fractionation----------------------------------------19 2.2.5 Purification of TOP1 and GST-fused TOP1 fragments------------------------19 2.2.6 Identification of calpain 2 cleavage sites in hTOP1, in vitro calpain cleavage assay and DNA relaxation analysis--------------------------------------20 2.2.7 Lentivirus-mediated small RNA interference (siRNA)-------------------------22 2.2.8 The coimmunoprecipitation (CoIP) assay-----------------------------------------23 2.2.9 Assays for human TOP1 cleavable complex (hTOP1cc)-----------------------24 2.2.10 Colony formation assay------------------------------------------------------------25 2.2.11 Quantitative and statistical analyses----------------------------------------------25 2.3 Results---------------------------------------------------------------------------------------27 2.3.1 Ca2+ influx promoted by calcium ionophores induces rapid and limited cleavage on human DNA topoisomerase I (hTOP1) ----------------------------27 2.3.2 Cytosolic protease(s) participates in Ca2+-activated cleavage of hTOP1-----28 2.3.3 Only calpains but not caspases, proteasome or de-novo synthesized proteases involve in Ca2+ influx mediated cleavage of hTOP1-----------------29 2.3.4 Calpain 2 has better proteolytic activity than calpain 1 on hTOP1------------30 2.3.5 Calpain 2 contributes to the Ca2+-activated hTOP1 proteolysis in vivo-------31 2.3.6 Ca2+ influx triggers nucleocytoplasmic shuttling of calpain 2------------------32 2.3.7 Nuclear entry of calpain2 is dependent on Ca2+ but not its catalytic activity--------------------33 2.3.8 Ca2+ induced nuclear entry of calpain 2 is regulated by calpastatin-----------33 2.3.9 Calpain 2 cleaves hTOP1 at two N’-terminal lysine residues, K158 and K183---------------34 2.3.10 Nucleolin interacts with two N-terminal truncated forms of hTOP1---------35 2.3.11 Calcium-influx mediated nucleolar accumulations of hTOP1 is independent of calpain 2 ---------------36 2.3.12 hTOP1tr proteins exhibit greater relaxation activity----------------------------37 2.3.13 Both two hTOP1tr are trapped on chromosome by CPT-----------------------38 2.3.14 Calpain 2 is involved in the ionomycin-induced protection from CPT Cytotoxicity-----------39 2.3.15 On hTOP1 HT29 cells has better basal proteolytic activity in which calpains may Involve---------------39 2.3.16 HT29 cells exhibits properties with more nuclear shuttling of calpain 2 and better resistant to CPT cytotoxicity------40 2.4 Summary-----------------------------------------------------------------------42 2.5 Discussions---------------------------------------------------------------------------------44 Chapter 3. Calcium influx-induced proteolytic cleavage of topoisomerase 2 beta---49 3.1 Introduction-------------------------------------------------------------------49 3.2 Materials and Methods------------------------------------------------------------------52 3.2.1 Drugs, chemicals, reagents and cell cultures--------------------------------------52 3.2.2 Transfection and preparation of cell extracts--------------------------------------52 3.2.3 Immunoblotting analysis (Western blotting)--------------------------------------53 3.2.4 Cellular fractionation assay---------------------------------------------------------53 3.2.5 Immunofluorescence assay (IFA)--------------------------------------------------54 3.2.6 Lentivirus-mediated small RNA interference (siRNA)-------------------------55 3.2.7 Colony formation assay-------------------------------------------------------------55 3.3 Results--------------------------------------------------------------------------------------57 3.3.1 Ionomycin-promoted Ca2+ influx causes rapid and limited proteolytic cleavage of hTOP2 beta---------57 3.3.2 Ca2+ dependent proteolytic processing of hTOP2 beta------------------------------57 3.3.3 Cleavage events of hTOP2 beta occurs in nucleus whereas cytosolic proteases have the most proteolytic activity on hTOP2 beta------58 3.3.4 Ca2+ influx-activated calpains including calpain 2 participate in the cleavage of hTOP2 beta-------------------------59 3.3.5 Calpastatin, a natural calpain inhibitor, reduces Ca2+-activated cleavage of hTOP2 beta-----------------61 3.3.6 Ca2+ influx-induced nuclear translocation of hTOP2 beta and down regulation of protein level of hTOP2 beta by calpain 2 contributes to the cell survival to VP-16 treatment (TOP2 poison)---------------------------62 3.4 Discussions---------------------------------------------------------------------------------63 4. Figures----------------------------------------------------------------------------------------65 Fig. 1 Human DNA topoisomerases and their expression throughout the cell cycle-----------------------------------------------------------------------------------66 Fig. 2 Human calpain family members---------------------------------------------------67 Fig. 3 Calpains associated diseases-------------------------------------------------------68 Fig. 4 Ionomycin-induced cleavage of hTOP1------------------------------------------69 Fig. 5 Detection of truncated hTOP1 with antibodies against different epitopes--70 Fig. 6 Ca2+ ionophores induced cleavage of hTOP1 in dosage and time course dependent manners-------------------------------------------------------------------71 Fig. 7 Ca2+ influx mediated proteolytic processing of hTOP1------------------------72 Fig. 8 Cytosolic extracts have the most proteolytic activity on hTOP1-------------73 Fig. 9 Only calpains but not caspases, proteasome or de-novo synthesized proteases involve in Ca2+ influx mediated cleavage of hTOP1-------------74 Fig. 10 Calpain 2 has better proteolytic activity than calpain 1 on hTOP1---------75 Fig. 11 Knockdown of calpain 2 represses cleavage of hTOP1----------------------76 Fig. 12 Ca2+ influx triggers the nuclear translocation of calpain 2-------------------77 Fig. 13 Ca2+ ionophore mediated nuclear translocation of calpain 2 in a dosage dependent manner----------------------------------------------------------------79 Fig. 14 Only EGTA not calpain inhibitor I could abolish nuclear shuttling of calpain 2----------------------------------------------------------------------------80 Fig. 15 Forced expression of calpastatin reduces cleavage of hTOP1 and nuclear accumulations of calpain 2------------------------------------------------------82 Fig. 16 Mapping calpain 2-mediated cleavage sites of hTOP1-----------------------83 Fig. 17 Construction of GFP-hTOP1 and its expression in HCT116 cells----------85 Fig.18 Nucleolin interacts with two N-terminal truncated forms of hTOP1-------86 Fig.19 Ca2+ influx mediated nucleolar accumulations of hTOP1 is independent of calpain 2--------------------------------------------------------------------------87 Fig. 20 N-terminal truncated hTOP1 has better supercoiling activity than full length of hTOP1--------------------------------------------------------------88 Fig. 21 Truncated forms of hTOP1 are trapped on chromosome by CPT-----------90 Fig. 22 Calpain 2 is involved in the ionomycin-induced protection from CPT cytotoxicity--------------------------------------------------------------------92 Fig. 23 Expression profiles of cellular calpain 1, 2 and hTOP1 proteins in different kinds of cancer cells---------------------------------------------------------------94 Fig. 24 On hTOP1 HT29 cells has better basal proteolytic activity in which calpains may involve--------------------------------------------------------------95 Fig. 25 HT29 cells exhibits properties with more nuclear shuttling of calpain 2 and better resistant to CPT cytotoxicity----------------------------96 Fig. 26 Diagram of Ca2+-mediated proteolytic processing of hTOP1---------------98 Fig. 27 Ca2+ influx induces proteolytic processing of hTOP2 beta--------------------100 Fig. 28 Cytosolic proteases contribute to the most efficiency of cleavage-------102 Fig. 29 Activated calpains including calpain 2 by Ca2+ influx are involved in the processing events of hTOP2 beta------------------------------------------103 Fig. 30 Ca2+ influx-mediated nucleolar accumulations of hTOP2 beta and down regulation of protein level of hTOP2 beta by calpain 2-----------------105 5. References----------------------------------------------------------------------106 6. Appendixes----------------------------------------------------------------------119 Appendix Fig. 1 Proteolytic responses of different proteins in HCT116 cells exposed to ionomycin------------------------------------------------120 Appendix Fig. 2 hTOP1tr has more unstable than full length of hTOP1 upon long term treatment of ionomycin----------------------------------------121 Appendix Fig. 3 CPT causes rapid degradation of ionomycin-induced hTOP1tr and Ca2+ influx retards CPT-mediated translocation of hTOP1------------------------------------------------------------------122 Appendix Fig. 4 Calpain is not involved in cisplatin-induced apoptosis in HCT116 cells----------------------------------------------------------124 Appendix Fig. 5 Calpain inhibitor I reduces VP-16-induced formation of apoptotic bodies and ionomycin-caused breakdown of nuclear membrane--------------------------------------------------------------125 7. Curriculum vitae--------------------------------------------------------------------------126 | |
| dc.language.iso | en | |
| dc.subject | 鈣蛋白酶 | zh_TW |
| dc.subject | 細胞質核穿梭 | zh_TW |
| dc.subject | 鈣離子 | zh_TW |
| dc.subject | 蛋白質降解 | zh_TW |
| dc.subject | 拓樸異構酶 | zh_TW |
| dc.title | 鈣離子如何活化切割拓樸異構酶的蛋白酶之研究 | zh_TW |
| dc.title | Study on calcium-induced proteolytic cleavage of DNA
topoisomerases | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 鄧述諄,周涵怡,沈湯龍,李明學 | |
| dc.subject.keyword | 鈣蛋白酶,拓樸異構酶,蛋白質降解,鈣離子,細胞質核穿梭, | zh_TW |
| dc.subject.keyword | Calpain,Topoisomerase,Proteolysis,Calcium,Nucleocytoplasmic shuttling, | en |
| dc.relation.page | 126 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2011-01-07 | |
| 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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