siRNA干扰CDKs对细胞周期和细胞凋亡的影响
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摘要
第一部分CDK1 siRNA干扰对细胞周期和细胞凋亡的影响
目的：研究CDK1 siRNA干扰抑制CDK1的表达及其对细胞周期和凋亡的影响。材料和方法：以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，脂质体转染CDK1 siRNA，分别用realtime-PCR、westernblot检测CDK1基因和蛋白的表达，AnnexinV／PI法检测转染细胞的凋亡，流式细胞术分析细胞周期阻滞，细胞进行瑞氏-姬姆萨染色后镜下观察其形态学变化结果：转染CDK1 siRNA后CDK1基因和蛋白的表达都下降。转染后24小时，CDK1蛋白表达已经下降，到转染后48小时、60小时，CDK1基因与蛋白都明显降低。转染CDK1 siRNA 48和60小时后的细胞周期G2／M期比例明显增加，而细胞凋亡率与对照相比没有明显升高。转染细胞经瑞氏-姬姆萨染色后，显微镜下看到双核细胞增多。结论：CDK1 siRNA干扰导致的CDK1表达降低只引起细胞周期G2／M期阻滞，细胞增殖减慢，没有导致细胞凋亡。
第二部分CDK1 siRNA干扰在Taxol诱导细胞凋亡中的作用
目的研究转染CDK1 siRNA在Taxol诱导细胞凋亡过程中的对细胞周期和凋亡的影响，探讨CDK1在细胞凋亡中的确切作用方法以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，脂质体转染CDK1 siRNA，转染后48小时加Taxol(20g／ml)刺激，实验设空白对照(未处理)、阴性对照(转染阴性siRNA)、空白对照加Taxol、阴性对照加Taxol、转染CDK1 siRNA、转染CDK1 siRNA加Taxol实验组。加药12小时后收集细胞，用AnnexinV／PI方法检测细胞的凋亡；流式细胞仪检测细胞DNA含量，分析细胞周期的变化；westernblot检测CDK1、BCL2蛋白的表达。结果CDK1蛋白表达水平在转染siRNA组都有明显降低。Taxol(20ug／ml)刺激12小时细胞出现明显G2／M期和S期阻滞以及细胞凋亡。细胞转染CDK1 siRNA后再用Taxol刺激，G2／M、S期阻滞效应和细胞的凋亡反应都没有明显改变。抗凋亡蛋白BCL2也只在加Taxol刺激组表达下降。结论siRNA干扰导致的CDK1表达降低对紫杉醇Taxol所诱导的细胞周期阻滞和细胞凋亡作用没有影响。
第三部分共转染CDK1、CDK2 siRNA对细胞周期和细胞凋亡的影响
目的研究共转染CDK1、CDK2 siRNA同时抑制CDK1、CDK2蛋白表达对细胞周期和凋亡的影响，探讨细胞周期主要调控分子在细胞凋亡中的确切作用。方法以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，用脂质体lipofactamihe2000同时转染CDK1和CDK2 siRNA。在转染后48、60小时收集细胞，用westernblot检测CDK1、CDK2蛋白的表达和抗凋亡蛋白Bcl2的表达，AnnexinV／PI检测转染细胞的凋亡，流式细胞术DNA含量检测分析细胞周期阻滞。AnnexinV／PI标记的细胞同时在激光共聚焦显微镜下观察凋亡细胞的形态；另外转染细胞进行瑞氏-姬姆萨染色后在普通光学显微镜下观察其形态变化。结果共转染CDK1、CDK2siRNA后48小时和60小时，WesternBlot结果显示CDK1和CDK2蛋白的表达都同时降低。共转染CDK1、CDK2 siRNA后，细胞周期在S期和G2／M期都出现阻滞，转染细胞经瑞氏-姬姆萨染色后在显微镜下可见双核或多核细胞增多；AnnexinV结果显示共转染CDK1、CDK2 siRNA的细胞在48小时和60小时都发生了明显的凋亡，激光共聚焦显微镜下的形态学观察也可见到早期凋亡和晚期凋亡的细胞，但westernblot结果显示凋亡蛋白Bcl2的含量没有明显改变。结论siRNA干扰导致的CDK1、CDK2表达同时降低不仅导致细胞周期S期和G2／M期的阻滞，抑制了细胞生长，也诱导了细胞凋亡。也间接说明CDK2可以替代CDK1的部分功能。
Part OneTHE INFLUENCE OF CDK1 siRNA INTERFERENCE ON CELL CYCLE AND APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: It is widely accepted fact that the balancebetween cell proliferation and apoptosis is important for tissue homeostasis. What is lesswell known, however, is that the molecular mechanism regulate the balance between cellproliferation and apoptosis. The family of cyclin-dependent kinase complexes (Cdks) arewell known for their role in the cell division cycle,but the precise role of Cdks in apoptosisremains to be defined. In order to investigate the relationship of the master regulators ineukaryotic cell cycle with apoptosis, in the present report, CDK1 siRNA was transfectedinto cells to inhibit the CDK1 gene expression and invesgate its influence on the cell cycleand cell apoptosis. METHODS: The siRNA targeting CDK1 gene was chemicallysynthesized and transfected into Hela cells or SW480 cell by lipofectamine2000. CDK1gene and protein expression level were examined by real-time PCR and westernblot,respectively. In order to demonstrate the change of the cell cycle and apoptosis aftertransfected, we used flow cytometry to detect the cell cycle and used Annexin V/P1technique to study on apoptosis. The morphological change of transfected cell wereexamined under microscopy by Wright-Giemsa stain. RESULTS: CDK1 gene wassuccessfully silenced by siRNA and the CDK1 protein expression level decreasedsignificantly, especially from 48 hour to 60 hour after transfection. The DNA contentanalysis showed that transfection of CDK1 siRNA leaded to cells accumulating in G2/Mphase. No apoptosis happened after transfection of CDK1 siRNA 48h or 60h. More doublenucleus or multi-nucleus cells could be seen under microscopy among the transfected cells.
CONCLUSION: The decreased CDK1 expression by gene silence leaded to cell cyclearrest in mitosis, but not induced apoptosis.
THE ROLE OF CDK1 siRNA INTERFERENCE IN TAXOL INDUCED APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: The cell cycle and the cell apoptosis wereintertwined. It was known from our research findings that after receiving apoptosis strikingonly those cells which were during cell cycle progression but not the GO phase cellunderwent apoptosis, we suppose maybe there are some molecular mechanism in cell cycleto regulate the cell apoptosis. This hypothesis prompted us to investigate the relationship ofthe master regulators in eukaryotic cell cycle with apoptosis. In the present report, CDK1siRNA was transfected into cells to interfere the CDK1 expression and invesgate itsinfluence on the taxol induced cell apoptosis, and elucidate the precise role of CDK1 in cellapoptosis. METHODS: The siRNA targeting CDK1 gene was chemically synthesized andtransfected into Hela cells or SW480 cell by lipofectamine2000. To make apoptosis striking,after 48 hours, the transfected cells were treated with 20ug/ml Taxol. Six experimentalgroups have been designed as follows: blank control which has not been treated、negativecontrol in which negative siRNA has been transfected、blank control stimulated byTaxol、negative control stimulated by Taxol、siRNA interfered CDK1、CDK1 silenced bysiRNA and then treated with Taxol. To detect cell cycle changes and apoptosis, we collectedthe cells 12 hours after drug treatment, used Annexin V/PI technique to study apoptosis,and flow cytometry to detect DNA content, thus the change of the cell cycle can be analyzed.The cell lysis were subjected to westernblot analysis for CDK1 and Bcl2 protein expressionchanging. RESULTS: CDK1 protein expression decreased in all siRNA transfected groups significantly. 20ug/ml taxol treatment induced cell apoptosis obviously and cell-cyclearrest in S phase、G2/M phase as early as 12h after addition of drug, while the degree ofits cell cycle arrest and apoptosis were not changed by CDK1 siRNA interference.Furthermore, the anti-apoptotic protein, Bcl-2 protein reduced only when apoptosis-inducing drug was added, but remained constant after transfection. The decrease of Bcl-2protein level related only with taxol treatment regardless of CDK1 siRNA transfection.
CONCLUSION: The decreased CDK1 activity by gene silencing did not change theinfluence of Taxol on cell cycle arrest and on apoptosis. It seems likely that Cdk1 mightnot be universally required for apoptosis in the same way that Cdk1 are universally requiredfor the cell cycle.
Part ThreeTHE INFLUENCE OF COTRANSFECTION CDK1 AND CDK2siRNA ON CELL CYCLE AND APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: Investigate of the influence of CDK1 andCDK2 siRNA cotransfection on cell cycle and apoptosis, to explore exact role of cell cyclemaster regulator in apoptosis. METHODS: The siRNA targeting the CDK1 and CDK2genes were synthesized and simultaneously cotransfected into Hela and SW480 cells bylipofectamine2000.48 and 60 hours after the cotransfection, CDK1 and CDK2 or Bcl2protein expressions were examined by westernblot. Cell cycle arrest was analyzed by flowcytometry. We detected apoptosis via the Annexin V/PI method. Study transfected cellmorphological changes under a microscope after Wright-Giemsa Stain. Laser scanningconfocal microscope (LSCM) was used to observe the morphologic changes of theapoptosis cells. RESULTS: CDK1 and CDK2 protein expression was depressed 48 and 60hours after cotransfection. Cotransfection of CDK 1 and CDK2 siRNA led to accumulationof cells in S and G2/M phases and severely triggered apoptosis. An increase of binucleate andmultinucleate cells was observed under the microscope.The morphological change of earlyphase and late phase apoptotic cells could be seen by LSCM,but the anti-apoptotic Bcl2protein level is constant. CONCLUSION: The decreased activities of CDK1 and CDK2 bygene silencing led not only to cell cycle arrest in S phase and G2/M phase, but also inducedapoptosis. It was indirectly tested that CDK2 could compensates for the functionof CDK1 when CDK1 was silenced by siRNA.
目的：研究CDK1 siRNA干扰抑制CDK1的表达及其对细胞周期和凋亡的影响。材料和方法：以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，脂质体转染CDK1 siRNA，分别用realtime-PCR、westernblot检测CDK1基因和蛋白的表达，AnnexinV／PI法检测转染细胞的凋亡，流式细胞术分析细胞周期阻滞，细胞进行瑞氏-姬姆萨染色后镜下观察其形态学变化结果：转染CDK1 siRNA后CDK1基因和蛋白的表达都下降。转染后24小时，CDK1蛋白表达已经下降，到转染后48小时、60小时，CDK1基因与蛋白都明显降低。转染CDK1 siRNA 48和60小时后的细胞周期G2／M期比例明显增加，而细胞凋亡率与对照相比没有明显升高。转染细胞经瑞氏-姬姆萨染色后，显微镜下看到双核细胞增多。结论：CDK1 siRNA干扰导致的CDK1表达降低只引起细胞周期G2／M期阻滞，细胞增殖减慢，没有导致细胞凋亡。
第二部分CDK1 siRNA干扰在Taxol诱导细胞凋亡中的作用
目的研究转染CDK1 siRNA在Taxol诱导细胞凋亡过程中的对细胞周期和凋亡的影响，探讨CDK1在细胞凋亡中的确切作用方法以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，脂质体转染CDK1 siRNA，转染后48小时加Taxol(20g／ml)刺激，实验设空白对照(未处理)、阴性对照(转染阴性siRNA)、空白对照加Taxol、阴性对照加Taxol、转染CDK1 siRNA、转染CDK1 siRNA加Taxol实验组。加药12小时后收集细胞，用AnnexinV／PI方法检测细胞的凋亡；流式细胞仪检测细胞DNA含量，分析细胞周期的变化；westernblot检测CDK1、BCL2蛋白的表达。结果CDK1蛋白表达水平在转染siRNA组都有明显降低。Taxol(20ug／ml)刺激12小时细胞出现明显G2／M期和S期阻滞以及细胞凋亡。细胞转染CDK1 siRNA后再用Taxol刺激，G2／M、S期阻滞效应和细胞的凋亡反应都没有明显改变。抗凋亡蛋白BCL2也只在加Taxol刺激组表达下降。结论siRNA干扰导致的CDK1表达降低对紫杉醇Taxol所诱导的细胞周期阻滞和细胞凋亡作用没有影响。
第三部分共转染CDK1、CDK2 siRNA对细胞周期和细胞凋亡的影响
目的研究共转染CDK1、CDK2 siRNA同时抑制CDK1、CDK2蛋白表达对细胞周期和凋亡的影响，探讨细胞周期主要调控分子在细胞凋亡中的确切作用。方法以人宫颈癌细胞株Hela细胞和人结肠癌细胞株SW480细胞为研究对象，用脂质体lipofactamihe2000同时转染CDK1和CDK2 siRNA。在转染后48、60小时收集细胞，用westernblot检测CDK1、CDK2蛋白的表达和抗凋亡蛋白Bcl2的表达，AnnexinV／PI检测转染细胞的凋亡，流式细胞术DNA含量检测分析细胞周期阻滞。AnnexinV／PI标记的细胞同时在激光共聚焦显微镜下观察凋亡细胞的形态；另外转染细胞进行瑞氏-姬姆萨染色后在普通光学显微镜下观察其形态变化。结果共转染CDK1、CDK2siRNA后48小时和60小时，WesternBlot结果显示CDK1和CDK2蛋白的表达都同时降低。共转染CDK1、CDK2 siRNA后，细胞周期在S期和G2／M期都出现阻滞，转染细胞经瑞氏-姬姆萨染色后在显微镜下可见双核或多核细胞增多；AnnexinV结果显示共转染CDK1、CDK2 siRNA的细胞在48小时和60小时都发生了明显的凋亡，激光共聚焦显微镜下的形态学观察也可见到早期凋亡和晚期凋亡的细胞，但westernblot结果显示凋亡蛋白Bcl2的含量没有明显改变。结论siRNA干扰导致的CDK1、CDK2表达同时降低不仅导致细胞周期S期和G2／M期的阻滞，抑制了细胞生长，也诱导了细胞凋亡。也间接说明CDK2可以替代CDK1的部分功能。
Part OneTHE INFLUENCE OF CDK1 siRNA INTERFERENCE ON CELL CYCLE AND APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: It is widely accepted fact that the balancebetween cell proliferation and apoptosis is important for tissue homeostasis. What is lesswell known, however, is that the molecular mechanism regulate the balance between cellproliferation and apoptosis. The family of cyclin-dependent kinase complexes (Cdks) arewell known for their role in the cell division cycle,but the precise role of Cdks in apoptosisremains to be defined. In order to investigate the relationship of the master regulators ineukaryotic cell cycle with apoptosis, in the present report, CDK1 siRNA was transfectedinto cells to inhibit the CDK1 gene expression and invesgate its influence on the cell cycleand cell apoptosis. METHODS: The siRNA targeting CDK1 gene was chemicallysynthesized and transfected into Hela cells or SW480 cell by lipofectamine2000. CDK1gene and protein expression level were examined by real-time PCR and westernblot,respectively. In order to demonstrate the change of the cell cycle and apoptosis aftertransfected, we used flow cytometry to detect the cell cycle and used Annexin V/P1technique to study on apoptosis. The morphological change of transfected cell wereexamined under microscopy by Wright-Giemsa stain. RESULTS: CDK1 gene wassuccessfully silenced by siRNA and the CDK1 protein expression level decreasedsignificantly, especially from 48 hour to 60 hour after transfection. The DNA contentanalysis showed that transfection of CDK1 siRNA leaded to cells accumulating in G2/Mphase. No apoptosis happened after transfection of CDK1 siRNA 48h or 60h. More doublenucleus or multi-nucleus cells could be seen under microscopy among the transfected cells.
CONCLUSION: The decreased CDK1 expression by gene silence leaded to cell cyclearrest in mitosis, but not induced apoptosis.
THE ROLE OF CDK1 siRNA INTERFERENCE IN TAXOL INDUCED APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: The cell cycle and the cell apoptosis wereintertwined. It was known from our research findings that after receiving apoptosis strikingonly those cells which were during cell cycle progression but not the GO phase cellunderwent apoptosis, we suppose maybe there are some molecular mechanism in cell cycleto regulate the cell apoptosis. This hypothesis prompted us to investigate the relationship ofthe master regulators in eukaryotic cell cycle with apoptosis. In the present report, CDK1siRNA was transfected into cells to interfere the CDK1 expression and invesgate itsinfluence on the taxol induced cell apoptosis, and elucidate the precise role of CDK1 in cellapoptosis. METHODS: The siRNA targeting CDK1 gene was chemically synthesized andtransfected into Hela cells or SW480 cell by lipofectamine2000. To make apoptosis striking,after 48 hours, the transfected cells were treated with 20ug/ml Taxol. Six experimentalgroups have been designed as follows: blank control which has not been treated、negativecontrol in which negative siRNA has been transfected、blank control stimulated byTaxol、negative control stimulated by Taxol、siRNA interfered CDK1、CDK1 silenced bysiRNA and then treated with Taxol. To detect cell cycle changes and apoptosis, we collectedthe cells 12 hours after drug treatment, used Annexin V/PI technique to study apoptosis,and flow cytometry to detect DNA content, thus the change of the cell cycle can be analyzed.The cell lysis were subjected to westernblot analysis for CDK1 and Bcl2 protein expressionchanging. RESULTS: CDK1 protein expression decreased in all siRNA transfected groups significantly. 20ug/ml taxol treatment induced cell apoptosis obviously and cell-cyclearrest in S phase、G2/M phase as early as 12h after addition of drug, while the degree ofits cell cycle arrest and apoptosis were not changed by CDK1 siRNA interference.Furthermore, the anti-apoptotic protein, Bcl-2 protein reduced only when apoptosis-inducing drug was added, but remained constant after transfection. The decrease of Bcl-2protein level related only with taxol treatment regardless of CDK1 siRNA transfection.
CONCLUSION: The decreased CDK1 activity by gene silencing did not change theinfluence of Taxol on cell cycle arrest and on apoptosis. It seems likely that Cdk1 mightnot be universally required for apoptosis in the same way that Cdk1 are universally requiredfor the cell cycle.
Part ThreeTHE INFLUENCE OF COTRANSFECTION CDK1 AND CDK2siRNA ON CELL CYCLE AND APOPTOSIS
Abstract BACKGROUND & OBJECTIVE: Investigate of the influence of CDK1 andCDK2 siRNA cotransfection on cell cycle and apoptosis, to explore exact role of cell cyclemaster regulator in apoptosis. METHODS: The siRNA targeting the CDK1 and CDK2genes were synthesized and simultaneously cotransfected into Hela and SW480 cells bylipofectamine2000.48 and 60 hours after the cotransfection, CDK1 and CDK2 or Bcl2protein expressions were examined by westernblot. Cell cycle arrest was analyzed by flowcytometry. We detected apoptosis via the Annexin V/PI method. Study transfected cellmorphological changes under a microscope after Wright-Giemsa Stain. Laser scanningconfocal microscope (LSCM) was used to observe the morphologic changes of theapoptosis cells. RESULTS: CDK1 and CDK2 protein expression was depressed 48 and 60hours after cotransfection. Cotransfection of CDK 1 and CDK2 siRNA led to accumulationof cells in S and G2/M phases and severely triggered apoptosis. An increase of binucleate andmultinucleate cells was observed under the microscope.The morphological change of earlyphase and late phase apoptotic cells could be seen by LSCM,but the anti-apoptotic Bcl2protein level is constant. CONCLUSION: The decreased activities of CDK1 and CDK2 bygene silencing led not only to cell cycle arrest in S phase and G2/M phase, but also inducedapoptosis. It was indirectly tested that CDK2 could compensates for the functionof CDK1 when CDK1 was silenced by siRNA.
引文
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1. Evan GI and Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001, 411: 342-9
2. Adamsen, B. L., et al., Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol, 2007. 31(6): 1491-500
3. Vermeulen, K., Z. N. Berneman, and D. R. Van Bockstaele, Cell cycle and apoptosis. Cell Prolif, 2003. 36(3): 165-75
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6. Michael Karin, Anning Lin. NF-(?)B at the crossroads of life and death.Nature Immunology. 2002,3: 221-227
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