本文選題：DNA + 依賴的蛋白激酶催化亞基��； 參考：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2016年碩士論文

【摘要】：DNA依賴的蛋白激酶催化亞基(DNA-dependent kinase catalytic subunit,DNA-PKcs)是一個分子量大約為460k D的蛋白激酶,其屬于磷脂酰肌醇-3-激酶相關(guān)蛋白激酶家族成員,是一種被DNA激活的絲氨酸/蘇氨酸激酶,其與KU70/KU80組成的異源二聚體調(diào)節(jié)亞基一起組成了異源三聚體DNA依賴的蛋白激酶(DNA-dependent kinase,DNA-PK)。DNA-PKcs的絲氨酸/蘇氨酸蛋白激酶活性不僅可以激活調(diào)節(jié)損傷修復(fù)的相關(guān)蛋白和參與細胞周期調(diào)控的蛋白,而且還可以通過自身活化的方法調(diào)節(jié)其激酶活性。研究證實DNA-PKcs是一個具有多功能性的酶,其最主要的也是人們研究最透徹的一個功能就是通過非同源末端修復(fù)途徑參與DNA雙鏈斷裂損傷修復(fù)。除此之外,DNA-PKcs的沉默或缺失還會引起電離輻射或化學(xué)藥物引起的細胞不正常的分裂,細胞非正常的G1期或G2/M期阻滯和自噬。近年來隨著對DNA-PKcs研究的不斷研究,發(fā)現(xiàn)其在腫瘤組織中的表達要超出正常范圍。很多研究已經(jīng)表明DNA-PKcs的抑制是一個增加腫瘤細胞對抗電離輻射,腫瘤試劑拓撲異構(gòu)酶II毒性物質(zhì)和順鉑等敏感性的非�？尚械姆椒�。有研究表明,DNA-PKcs在膠質(zhì)瘤細胞中參與電離輻射誘發(fā)自噬的調(diào)節(jié),但是關(guān)于DNA-PKcs如何調(diào)節(jié)自噬的研究很少。細胞自噬是真核細胞中非常關(guān)鍵且保守的物質(zhì)的分解與循環(huán)利用的過程,有助于降解細胞內(nèi)長壽命的蛋白質(zhì),細胞溶質(zhì)的成分,損傷老化的細胞器以及某些病原體使得它們得以循環(huán)重復(fù)利用,從而有助于保持細胞的內(nèi)穩(wěn)態(tài),這是自噬最基本的作用。在面對錯亂復(fù)雜的環(huán)境比如必需營養(yǎng)物質(zhì)的缺乏,電離輻射以及內(nèi)源性的活性氧,復(fù)制壓力等,機體的細胞需要作出各種反應(yīng)來應(yīng)對不利環(huán)境,自噬會通過消耗自身的物質(zhì)來使細胞獲得臨時的供應(yīng)從而促進細胞存活。但是,細胞自噬在腫瘤的治療過程中依然是一個十分有爭議的話題,因為自噬可以刺激細胞存活,也可以誘導(dǎo)細胞死亡。研究表明當(dāng)細胞遭遇某一種生理變化或者某一種特殊的處理比如致死性的藥物劑量,細胞自噬就可以促進細胞的死亡。研究證實自噬的功能失調(diào)與許多疾病的起始和發(fā)展有很大關(guān)系。3-甲基腺嘌呤(3-methyladenine,3MA)是一個被研究學(xué)者廣泛使用的細胞自噬抑制劑,主要作用能夠通過抑制細胞自噬的正性調(diào)節(jié)子Ⅲ型PI3K來抑制自噬。目的1.以DNA-PKcs敲低的He La細胞系為對象,觀察照射后細胞的放射敏感性以及自噬蛋白的表達情況,探討DNA-PKcs調(diào)節(jié)自噬作用及其可能的分子機制;2.電離輻射可以誘發(fā)宮頸癌He La細胞G2/M期的周期阻滯,探討自噬抑制劑3-甲基腺嘌呤在電離輻射誘發(fā)He La周期阻滯中的調(diào)節(jié)作用。方法利用實驗室前期構(gòu)建的DNA-PKcs沉默的表達載體,采用慢病毒介導(dǎo)的小干擾RNA技術(shù),通過Lipofectamin 2000作為介質(zhì),包裝慢病毒顆粒并感染He La細胞,使用嘌呤霉素抗性篩選獲得穩(wěn)定敲低DNA-PKcs的宮頸癌He La細胞系,并且經(jīng)過免疫印跡鑒定;Hela-sh NC和Hela-sh DNA-PKcs經(jīng)過單獨照射或者與自噬的抑制劑3-甲基腺嘌呤聯(lián)合作用處理細胞,在照射后不同時間點(0、12、24、48和72h)采用細胞增殖與毒性試驗檢測細胞的增殖與細胞的放射敏感性變化;He La細胞經(jīng)過單獨照射或者與自噬的抑制劑3-甲基腺嘌呤聯(lián)合作用處理,通過細胞平板克隆形成實驗檢測照射后He La-sh NC和He La-sh DNA-PKcs在不同劑量射線下存活率變化;通過流式細胞術(shù)檢測6Gy照射后0、2、4、6、8和12h后的細胞周期變化及有絲分裂期磷酸化組蛋白H3的變化;DNA-PKcs的激酶抑制劑NU7026與自噬的激動劑雷帕霉素共同處理細胞并通過免疫印跡實驗檢測多功能的泛素結(jié)合蛋白P62、微管輕鏈蛋白LC3、哺乳動物雷帕霉素的靶蛋白m TOR并且He La經(jīng)過單獨照射或者與自噬的抑制劑3-甲基腺嘌呤聯(lián)合作用處理,通過免疫印跡檢測周期檢驗點激酶2(Chk2),Cdk1及磷酸化酶Cdc25C的變化;利用分子克隆技術(shù)構(gòu)建GFP-LC3表達載體并通過激光共聚焦免疫熒光技術(shù)檢測綠色熒光GFP-LC3焦點的形成。結(jié)果1.免疫印跡驗證He La-sh NC和He La-sh DNA-PKcs,發(fā)現(xiàn)DNA-PKcs在敲低細胞中表達很少,這說明DNA-PKcs穩(wěn)定敲低的細胞系構(gòu)建成功;2.細胞增殖與毒性檢測結(jié)果顯示,DNA-PKcs敲低的細胞放射敏感性增強,細胞的增殖速度減慢;在照射處理的基礎(chǔ)上在細胞中加入自噬的抑制劑3-甲基腺嘌呤,無論是對照細胞還是DNA-PKcs敲低的細胞,其細胞的放射敏感性進一步增強;3.免疫印跡結(jié)果得到:與Hela-sh NC而言,DNA-PKcs敲低的細胞中,微觀相關(guān)蛋白LC3蛋白表達增多而p62蛋白表達減少,m TOR在2481位點的磷酸化水平下調(diào);4.使用自噬的激動劑雷帕霉素和DNA-PKcs的激酶抑制劑NU7026處理Hela細胞,通過免疫印跡實驗得到DNA-PKcs的激酶活性被抑制后,細胞自噬蛋白LC3表達增加且加入雷帕霉素后自噬水平進一步增加;5.激光共聚焦免疫熒光法得到DNA-PKcs蛋白敲低后,平均每個細胞的GFP-LC3熒光斑點數(shù)目增多,加入自噬的抑制劑3MA細胞自噬被抑制,加入自噬促進物RAPA,細胞自噬增加;6.細胞經(jīng)過6Gy照射處理并通過流式細胞術(shù)檢測在照射后不同時間細胞周期的變化,發(fā)現(xiàn)細胞周期被阻滯在G2/M期,這與實驗室前期的實驗結(jié)果一致;在照射的基礎(chǔ)上輔以自噬的抑制劑3-甲基腺嘌呤發(fā)現(xiàn)細胞的阻滯現(xiàn)象被破壞,這說明3MA參與了電離輻射誘導(dǎo)的周期阻滯的調(diào)節(jié);7.細胞經(jīng)過照射和自噬的抑制劑3-甲基腺嘌呤共同處理,通過流式細胞術(shù)檢測3-甲基腺嘌呤處理后磷酸化的組蛋白H3表達增多,這說明3MA可以促進細胞從G2期進入到M期;8.免疫印跡檢測在不同的時間點細胞周期相關(guān)蛋白,發(fā)現(xiàn)在加入自噬的抑制劑3-甲基腺嘌呤后,磷酸化的ATM(S1981)、Chk2(T68),Cdc2(T15)和Cdc25C(S216)蛋白的水平均有所下調(diào)。結(jié)論1.DNA-PKcs蛋白敲低后細胞的放射敏感性增加且電離輻射誘發(fā)的細胞自噬增加;2.DNA-PKcs可能是通過m TOR信號通路來調(diào)節(jié)自噬;3.3-甲基腺嘌呤通過ATM/Chk2/Cdc25c/Cdk1的信號通路來調(diào)節(jié)電離輻射誘發(fā)的細胞周期G2/M檢查點功能。
[Abstract]:DNA dependent protein kinase catalytic subunit (DNA-dependent kinase catalytic subunit, DNA-PKcs) is a protein kinase with a molecular weight of approximately 460k D, belonging to a member of the phosphatidyl inositol -3- kinase related protein kinase family, a serine / threonine kinase activated by DNA, and a heterogenous two polymer modulating subunit consisting of KU70/KU80. The serine / threonine protein kinase activity of the DNA-dependent kinase (DNA-PK).DNA-PKcs dependent protein kinase (kinase, DNA-PK).DNA-PKcs not only activates the related proteins that regulate the damage repair and the proteins involved in the cell cycle regulation, but also can regulate the activity of the kinase through the method of self activation. The study confirms that DNA -PKcs is a multifunctional enzyme, and its most important function is to participate in the repair of DNA double strand breaks through a non homologous terminal repair pathway. In addition, the silence or deletion of DNA-PKcs may cause abnormal division of cells induced by ionizing radiation or chemical drugs, and the cells are abnormal. G1 phase or G2/M phase block and autophagy. In recent years, with the continuous study of DNA-PKcs research, it has been found that its expression in the tumor tissue is beyond the normal range. Many studies have shown that the inhibition of DNA-PKcs is an increase in the sensitivity of tumor cells to ionizing radiation, the tumor reagent topoisomerase II toxic substances and cisplatin. Method. Studies have shown that DNA-PKcs is involved in the regulation of autophagy induced by ionizing radiation in glioma cells, but there is little research on how DNA-PKcs regulates autophagy. Cell autophagy is the process of decomposition and recycling of very critical and conservative substances in eukaryotic cells, which can help to degrade proteins and cells with long life in cells. The components of the solute, the aging of the organelles and some pathogens make them circulate and reuse them, thus helping to maintain the homeostasis of the cells, which is the most fundamental role of autophagy. In the face of the complex and complex environment such as the lack of essential nutrients, ionizing radiation, endogenous reactive oxygen species, and the reproduction of pressure, Cells need to respond to adverse circumstances, and autophagy can help cells to survive by consuming their own substances to facilitate cells to survive. However, autophagy remains a very controversial topic in the treatment of tumors, because autophagy can stimulate cell survival and induce cell death. Studies have shown that cell autophagy can promote cell death when a cell is subjected to a certain physiological change or a particular treatment, such as a lethal dose of drug. The study confirms that the dysfunction of autophagy has a great relationship with the initiation and development of many diseases..3- methyl adenine (3-methyladenine, 3MA) is a widely studied scholar. A ubiquitous cellular autophagy inhibitor, which can inhibit autophagy by inhibiting the positive regulator of autophagy PI3K to inhibit autophagy. Objective 1. to observe the radiosensitivity of the cells and the expression of autophagy after exposure to the DNA-PKcs knockout He La cell lines, and to explore the role of DNA-PKcs to regulate autophagy and its possible molecules. Mechanism: 2. ionizing radiation can induce the periodic block of the G2/M phase of He La cells in cervical cancer, and explore the regulating role of the autophagy inhibitor 3- methyl adenine in the He La cycle arrest induced by ionizing radiation. Methods using the DNA-PKcs silent expression vector constructed in the early laboratory, the small interference RNA technology mediated by the slow disease virus, through Lipofectamin, through Lipofectamin, through Lipofectamin. 2000 as a medium, the lentivirus particles were packed and infected with He La cells. The He La cell line of the cervical cancer that had a stable knock down DNA-PKcs was screened using the resistance of purinomycin resistance, and was identified by immunoblotting; Hela-sh NC and Hela-sh DNA-PKcs were irradiated individually or combined with the autophagy inhibitor 3- methyl adenine. After different time points (0,12,24,48 and 72h), cell proliferation and cytotoxicity test were used to detect cell proliferation and cell radiosensitivity. He La cells were irradiated individually or combined with autophagic inhibitor 3- methyl adenine, and cell plate cloning was used to test the He La-sh NC and He La-sh DNA-PKcs after irradiation. The change of survival rate under different doses of radiation; cell cycle changes of 0,2,4,6,8 and 12h after 6Gy irradiation by flow cytometry and changes in phosphorylated histone H3 during mitosis; DNA-PKcs kinase inhibitor NU7026 and autophagy agonist rapamycin were treated together and multifunctional flooding was detected by immunoblotting. The peptide binding protein P62, microtubule light chain protein LC3, mammalian target protein M TOR of rapamycin and He La were irradiated individually or combined with autophagic inhibitor 3- methyl adenine, and the changes in periodic test point kinase 2 (Chk2), Cdk1 and phosphorylase Cdc25C were detected by immunoblotting, and GFP-LC3 was constructed by molecular cloning technology. The expression vector was expressed by the laser confocal immunofluorescence technique to detect the formation of the focus of green fluorescent GFP-LC3. Results 1. Western blot verified He La-sh NC and He La-sh DNA-PKcs, and found that DNA-PKcs was rarely expressed in the knockout cells, which indicated that the cell lines with a stable and low level of low DNA-PKcs were constructed successfully; 2. cell proliferation and toxicity detection showed, DNA-P, DNA-P. The radiosensitivity of the Kcs knockout cells increased and the cell proliferation slowed down; 3- methyl adenine, an inhibitor of autophagy, was added to the cells on the basis of irradiation treatment, whether the control cells or the DNA-PKcs knockout cells, the radiosensitivity of the cells was further enhanced; 3. the results of immunoblotting were obtained with Hela-sh NC, DNA-PKcs In the lower knockout cells, the expression of microprotein LC3 protein was increased and the expression of p62 protein decreased, and the phosphorylation level of M TOR was downregulated at 2481 site. 4. the Hela cells were treated with the autophagic agonist, rapamycin and DNA-PKcs kinase inhibitor NU7026, and the kinase activity of DNA-PKcs was inhibited by immunoblotting, and the autophagic eggs of the cells were autophagy. The expression of white LC3 was increased and the autophagy level was further increased after the addition of rapamycin. 5. laser confocal immunofluorescence showed that the number of GFP-LC3 fluorescence spots in each cell increased, the autophagy of 3MA cells added to autophagy was inhibited, autophagy promoted RAPA, autophagy increased, and 6. cells were illuminated by 6Gy. The cell cycle of the cell cycle was detected by flow cytometry and the cell cycle was detected at different time after irradiation. It was found that the cell cycle was blocked in the G2/M phase, which was in accordance with the experimental results in the early laboratory. On the basis of the irradiation, the inhibitor of autophagy, 3- methyl adenine, found that the cell block was destroyed, which indicates that 3MA is involved in the ionizing radiation. The regulation of induced periodic block; 7. cells were treated with 3- methyl adenine, an inhibitor of irradiation and autophagy, and the expression of histone H3 in the phosphorylation of 3- methyl adenine was increased by flow cytometry, indicating that 3MA could promote cells to enter M phase from G2 phase; and 8. blot detection at different time points in cell cycle phase The levels of phosphorylated ATM (S1981), Chk2 (T68), Cdc2 (T15) and Cdc25C (S216) protein were all downregulated after the autophagy inhibitor 3- methyl adenine was added. Conclusion the radiosensitivity of the cells increased and the cell autophagy induced by ionizing radiation increased after the 1.DNA-PKcs protein knockdown; 2.DNA-PKcs may be through the m signaling pathway. To regulate autophagy, 3.3- methyladenine regulates the G2/M checkpoint function of ionizing radiation induced cell cycle through ATM/Chk2/Cdc25c/Cdk1 signaling pathway.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R818

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