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研究生:黃琇琴
研究生(外文):Hsiu-Chin Huang
論文名稱:熱休克蛋白質90之生化特性及其抑制劑-膠達納黴素對COS-7細胞之分子效應
論文名稱(外文):Biochemical characterization of porcine heat shock protein-90 and the molecular effects of its inhibitor-geldanamycin on COS-7 cells
指導教授:劉銀樟
指導教授(外文):Yin-Chang Liu
學位類別:博士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2001
畢業學年度:90
語文別:中文
論文頁數:110
中文關鍵詞:熱休克蛋白質90膠達納黴素
外文關鍵詞:heat shock protein-90trichostatin-Ageldanamycin
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在過去的實驗中,我們發現因肥厚性心肌病而猝死的豬,牠心肌內的HSP90有大量減少的現象。這是第一次有證據顯示HSP90的減少與肥厚性心肌病有關。為了更進一步了解HSP90的生化特性,我們選殖豬hsp90的cDNA,並測試其是否具有熱誘發的特性。並進一步,測試其自體磷酸化及被磷酸化的能力。而且,利用HSP90的抑制劑-膠達納黴素(GA, geldanamycin)研究是否GA在試管中或細胞中具有阻斷HSP90功能的能力。
豬熱休克蛋白質90之cDNA序列已分析出來,共有2202個nucleotide。豬之hsp90 cDNA序列與人類比對之結果有88.6%之相似性;而amino acid 序列之相似性則高達99.7%。733個amino acid 中只有三個不同。細胞株經43℃加熱處理30分鐘後,hsp90的基因表現大量增加,此外,發現有三種不同的轉錄長度,估計分別為2.2,3.0,及4.1kb。全豬經43℃加熱處理30分鐘後,心臟、腎臟及肝等器官HSP90之mRNA表現量均有增加(以RT-PCR及Northern分析)。唯獨腦原有之量較其他組織高,經加熱處理後並未增加。HSP90蛋白質在各個器官的表現以西方轉漬法分析發現,腦下垂體、腦、腎上腺和睪丸含量較高。
為了實驗所需,運用Q-Sepharose 和hydroxyapatite (HA) column純化豬睪丸內的熱休克蛋白質90(HSP90),以生產抗HSP90的抗體。經兩隻column純化後的90-kDa蛋白質進一步自電泳膠片上切下並electroelution。此90-kDa蛋白質以市售之抗HSP90抗體雜交,証實為HSP90。以此蛋白質注射兔子所產生之抗體以西方轉漬法分析具有高專一性。由電泳膠片所切下純化之HSP90 與[γ-32P]ATP.Mg2+作用並無自體磷酸化反應,但可作為數種磷酸激脢之受質而使其磷酸化。此數種磷酸激脢磷酸化HSP90的程度為PKA=CKII>AK>>kinase FA/GSK-3a。此外,我們也測試GA是否可抑制HSP90的磷酸化,結果並不行。但heparin可以。顯示以HA純化的HSP90帶有少量的CKII。而且高溫也會使HSP90喪失磷酸化能力。所以根據這些結果,HA純化的HSP90應不具有自體磷酸化的能力。
在前面的實驗中無法看出GA對HSP90功能上的影響。因此。我們運用trichostatin A (TSA)-組蛋白去乙醯化脢(histone deacetylase)抑制劑,處理COS-7細胞,看GA是否會影響TSA 所造成的細胞功能上的改變。當把50 ng/ml TSA加入COS-7細胞時,24小時後,細胞存活率只有20%,但是經過0.5 mg/ml GA前處理半小時,再加TSA處理24小時(TSA+GA),可使細胞存活率達40%。而且可發現TSA處理的細胞於藥物處理8小時後出現DNA片段(DNA fragmentation) (細胞凋亡的證據之一),細胞凋亡的比例高達15-20%。而有GA前處理的細胞凋亡比例只有6%。此外,GA前處理使得TSA所誘發的histone H4超乙醯化及GFP的表現程度降低。經西方轉漬法分析證實,GA處理後的細胞,熱休克蛋白質70(HSP70)大量增加;處理後的8小時可達2到3倍,20小時則可達5到7倍。但是熱休克蛋白質90並未增加,因此,我們認為GA抑制TSA所造成的細胞凋亡是由於HSP70大量增加,以至於對細胞產生保護作用所致。
In a previous study (Lee et al., 1996), we found that the expression of HSP90 in cardiac tissue was substantially reduced in sudden-death pigs with hypertrophic cardiomyopathy (HCM). This was the first evidence correlating a reduced HSP90 level in ventricular tissue with cardiac arrest in HCM pigs. To realize the biochemical characterization, we cloned porcine hsp90 cDNA and determined its heat-inducibility. In addition, we further purified HSP90 to test its phosphorylation ability and using geldanamycin (GA), an inhibitor of HSP90, to study if GA indeed blocks HSP90 function in vitro and in vivo.
We have isolated and sequenced cDNA clones encoding a 90-kDa heat shock protein (HSP90) from a porcine brain cDNA library. The sequence of the 2,202- nucleotide coding region showed 88.6% homology with that of the human homologue. Moreover, the deduced amino acid sequence of the porcine hsp90 cDNA was 99.7% identical to that of the human counterpart, with differences of only three amino acids in a total of 733 residues. Expression of the gene was greatly elevated in cultured cells during recovery from heat shock treatment at 45℃ for 60 min. Three major transcripts with 2.2, 3.0, and 4.1 kb in size were detected by Northern blot hybridization. These transcripts were further identified in a whole pig hyperthermia experiment. These three hsp90 transcripts were constitutively expressed in porcine tissues including kidney, liver, brain, and heart, and their levels were markedly enhanced during recovery from 30 min hyperthermia treatment at 43℃. Furthermore, we found that HSP90 was preferentially expressed in pituitary gland, brain, adrenal gland, and testis, in comparison to the other tissues.
Therefore, we purified a large quantity of HSP90 from porcine testis by hydroxylapatite (HA-HSP90) and SDS-PAGE/electroelution (eluted-HSP90) to explore the molecular mechanism of HSP90 phosphorylation affecting its metabolism. The purified HSP90 was used as an antigen to raise polyclonal antibodies in rabbits. Immunoblot analysis revealed that most purified HSP90 was HSP90a. Incubation of the purified HSP90 or HSP90 immunoprecipitated from extracts of human A431 cells, Balb/c 3T3 fibroblasts, and porcine testis with [γ-32P]ATP.Mg2+ resulted in phosphorylation of HSP90. However, the eluted-HSP90 lost its phosphorylation ability when incubated with [γ-32P]ATP.Mg2+ alone but could be phosphorylated by various protein kinases. The order of phosphorylation of HSP90 by these kinases is PKA = CKII > AK >> kinase FA/GSK-3α. Geldanamycin (GA) is HSP90-specific inhibitor, which binds the ATP-binding site of HSP90. Therefore, we test if GA could inhibit the phosphorylation of HA-HSP90. The result showed that GA did not inhibit the phosphorylation of HA-HSP90. However, heparin severely inhibited the phosphorylation. This result implied that the phosphorylation of HA-HSP90 was due to the associated CKII. Moreover, high temperatures almost completely inhibited the phosphorylation of HA-HSP90. Accordingly, we suggest that the HA-HSP90 cannot autophosphorylate in our system.
The phosphorylated function of HSP90 did not affect by GA in our in vitro system. Therefore, we use COS-7 cells as our in vivo system to test whether GA affect the cellular functions in trichostatin A (TSA)-treated cells. TSA is an inhibitor of histone deacetylase, results in histone H4 hyperacetylation and cell cycle arrest. When using TSA treatment, although caused COS-7 cell death, pretreatment of 0.5 mg/ml GA for 30 min and an addition of 50 ng/ml TSA (GA+TSA) apparently averted cell death. Our results indicated that the cell survival rate was only approximately 20% when prolonged treatment was undertaken with 50 ng/ml TSA (TSA) alone for 24 h. In contrast, the cell survival rate was enhanced by two folds when treating with GA+TSA. Furthermore, DNA fragmentation assay revealed that fragmented DNA was produced 8 h after prolonged treatment with TSA alone. Within 16 h, the apoptotic percentages of TSA-treated cells were between 15-25%. In contrast, the other treatments did not exceed 6%. Furthermore, GA inhibited TSA-induced histone H4 hyperacetylation. Western blotting analysis further demonstrated that the HSP70 levels did not significantly increase in TSA-treated cells. However, the accumulated 70-kDa heat shock protein (HSP70) markedly increased up to 2 to 3 folds at 8 h in GA- and GA+TSA-treated cells, and the maximum amount up to 5 to 7 folds at 20 h. Conversely, HSP90 did not markedly increase in all treatments. Based on the results in this study, we suggest that apoptosis induced by TSA can be prevented by GA-induced increment of heat shock proteins, particularly HSP70.
謝………………………………………………………………………….1
Abbreviation……………………誌……………………………………………2
Abstract………………………………………………………………………4
中文摘要…………………………………………………………………….7
Publication list……………………………………………………………….9
Chapter 1: General introduction……………………………………………...11
Chapter 2: Molecular cloning and characterization of porcine cDNA encoding a 90-kDa heat shock protein and its expression following hyperthermia………………………………………….20
Chapter 3: Purification and characterization of porcine testis 90-kDa heat shock protein (HSP90) as a substrate for various protein kinases…………………………………………………………...41
Chapter 4: Geldanamycin inhibits trichostatin A-induced cell death and histone H4 hyperacetylation in COS-7 cells……………………..69
Chapter 5: Conclusion and perspective………………………………………89
Chapter 6: Literatures cited…………………………………………………..94
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