mTOR信号通路在细胞生长调控中的作用与机制研究
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摘要
mTOR(the mammalian target of rapamycin)是一种存在于哺乳动物细胞中的Ser/Thr激酶,可以汇聚和整合来自于营养、生长因子、能量和环境胁迫对细胞的刺激信号,进而调节细胞生长。mTOR信号通路影响胚胎干细胞和早期胚胎的发育,并且与肿瘤、肥胖及代谢紊乱等疾病有关。目前已开展mTOR信号通路研究的有人及小鼠、大鼠、牛等哺乳动物。由于缺乏基本的基因、表达及功能方面的研究数据,mTOR信号通路在羊细胞中的研究尚属空白。本课题选择研究较多的人肿瘤细胞为模式细胞,意图通过对模式细胞的研究为下一步开展绒山羊细胞研究作好技术准备,同时将两种细胞作为比对,相互参照,证明mTOR信号通路在细胞生长调节中的关键性作用。
一、mTOR信号通路在人肿瘤细胞生长调控中的作用与机制
1.人食道癌细胞SEG-1和人正常食道上皮细胞KOB-13中mTOR基因和TSC2基因的克隆与表达检测
mTOR激酶是mTOR信号通路的中心协调器,TSC2是mTOR的上游负调节因子,它们在细胞中的活性与细胞生长调控密切相关。通过RT-PCR从人食道癌细胞SEG-1中和人食道正常上皮细胞KOB-13中分别克隆到了mTOR基因和TSC2基因的cDNA片段并比较了两个基因在两种细胞中的表达情况。结果表明:mTOR基因和TSC2基因在肿瘤细胞SEG-1中高表达。
2.mTOR抑制对SEG-1细胞生长的影响及机制
使用mTOR特异性抑制剂RAD001处理SEG-1细胞,结果显示SEG-1细胞对RAD001敏感。mTOR抑制可引起SEG-1细胞周期阻滞,细胞形态发生改变,抑制细胞增殖甚至导致细胞死亡。mTOR被抑制可强烈抑制其下游靶S6的磷酸化,同时还抑制mTOR、S6K1和S6基因的表达,且这些抑制效应都具有剂量依赖关系。结果表明:RAD001抑制mTOR信号通路的活性,通过抑制mTOR及其下游靶S6的磷酸化和相关基因的表达抑制细胞生长。
3.FAK/IGF-IR与mTOR信号通路的关系
利用FAK和IGF-IR抑制剂TAE226处理人食道癌细胞SEG-1,结果显示SEG-1细胞对TAE226十分敏感。TAE226对SEG-1细胞具有细胞毒性,可使得细胞形态发生明显改变,抑制增殖并可引起细胞死亡,且具有剂量依赖效应。FAK/IGF-IR被抑制,可导致Akt、mTOR、S6K1和S6磷酸化的强烈抑制,同时抑制相应基因的表达。结果表明:TAE226对FAK和IGF-IR的抑制导致了mTOR信号通路活性的强烈抑制,预示FAK可能是mTOR信号通路的调节因子。
二、绒山羊细胞中mTOR信号通路的功能与作用机制
1.内蒙古白绒山羊mTOR信号通路相关蛋白基因的克隆与基本表达模式分析
克隆了内蒙古白绒山羊mTOR基因约8.6Kb的全长cDNA及S6K1、S6K2、S6和FAK基因的部分cDNA片段,序列分析表明几个基因在进化上都是高度保守的。表达模式分析表明mTOR基因、S6K1基因和S6K2基因在脾、肾、睾丸和肌肉中都有表达,在肾中表达稍强,脾中稍弱;S6基因在脾、睾丸和肌肉中都高表达;FAK基因在脾、睾丸和肌肉中都有表达,在睾丸中稍弱一些。这些基因序列和表达模式数据都是首次获得,为开展进一步的研究奠定了基础。
2.mTOR信号通路在绒山羊胎儿成纤维细胞生长调控中的作用与机制
使用mTOR特异性抑制剂CCI-779处理内蒙古白绒山羊胎儿成纤维细胞(GFb),结果表明GFb对CCI-779敏感,CCI-779对GFb具有细胞毒性。CCI-779处理可导致细胞生长抑制,在24小时内引起细胞死亡。mTOR抑制可引起GFb细胞周期阻滞,细胞骨架失去正常组织结构,形态发生明显改变。CCI-779微弱抑制mTOR的磷酸化,强烈抑制S6的磷酸化,同时还抑制mTOR、Akt、S6K1和S6基因的表达,并可引起35KD Caspase-3酶原量减少,且这些抑制均具有剂量依赖效应。结果表明:CCI-779抑制mTOR信号通路的活性,抑制细胞增殖。mTOR被抑制不仅影响其下游S6的磷酸化,而且抑制Akt、S6K1和S6基因的表达,并可能具有诱导绒山羊胎儿成纤维细胞凋亡的作用。
综上所述,本研究首次对mTOR信号通路在绒山羊细胞生长调节中的作用进行研究,克隆了内蒙古白绒山羊mTOR、S6K1、S6K2、S6和FAK基因并研究其基本表达模式,证明了mTOR信号通路存在于绒山羊胎儿成纤维细胞中并调控细胞生长。通过对人肿瘤细胞和内蒙古白绒山羊胎儿成纤维细胞的研究,并将对两种细胞的研究结果进行综合分析,认为mTOR信号通路调控细胞生长的可能机制为:mTOR蛋白激酶被抑制后,通过调节下游靶S6K1和S6的磷酸化及相关基因的表达调控细胞生长。
The mammalian target of rapamycin (mTOR) is a kind of Ser/Thr kinase in mammalian cells. It can recruit and integrate input signals from nutrients, growth factors, energy and environmental stress to regulate cell growth and proliferation via different cellular processes. The mTOR signaling pathway also affects the development of the embryonic stem cells (ESCs) and early embryo, and involved in cancers and metabolism disease. The mTOR signaling pathway has been investigated extensively in human, mouse, rat and cattle, whereas it is not yet studied in goat due to the lack of basic data about genes, gene expression and function. Thus this study uses the human tumor cells as a model to compare with the results from goat to prove that the mTOR signaling pathway plays a critical role in cell proliferation regulation.
1 Function and mechanism of mTOR signaling pathway in regulation of human cancer cells growth
1.1 Cloning and expression of mTOR and TSC2 genes in human esophageal cancer cells and primary normal esophageal epithelial cells
mTOR and TSC2 are two of the most important protein kinases within mTOR signaling pathway related with regulation of cell growth. mTOR is a central regulator in the pathway, and TSC2 works as a negative regulator to mTOR. mTOR cDNA segment and TSC2 cDNA segment were cloned by RT-PCR from human esophageal cancer cells(SEG-1) and primary normal esophageal epithelial cells (KOB-13). The expression of mRNA and proteins between these two kinds of cells were compared by RT-PCR and Western blot, separately. The results showed that the genes overexpressed in SEG-1 cells.
1.2 Effect and mechanism of mTOR inhibition on SEG-1 cells growth
SEG-1 cells were treated with RAD001, a specific inhibitor of mTOR and the results showed that SEG-1 cells are sensitive to RAD001 compared to the control group. RAD001 is cytotoxic to SEG-1 cells, and lead to death of the cells and inhibited cell proliferation. The shape of the cells changed and G1/S cell cycle was arrested by mTOR inhibition. RAD001 weakly inhibited phosphorylation of mTOR, and strongly inhibited phosphorylation of its downstream target S6 while the expression of mTOR、S6K1 and S6 genes were inhibited. The inhibitions depended on dosage of the inhibitor. The results showed that RAD001 inhibits activity of mTOR signal pathway. mTOR inhibition induces mTOR and S6 phosphorylation inhibited, and inhibits the expression of the genes.
1.3 The relationship between the FAK/IGF-IR and the mTOR signaling pathway
TAE266, a dual inhibitor for FAK and IGF-IR, was used to treat SEG-1 cells. SEG-1 cells were sensitive to TAE266 and TAE226 had lethal function to SEG-1 cells. The cells shape was changed distinctly and cell proliferation was inhibited by the inhibitor with dose-dependant effect. The phosphorylation of mTOR, Akt and S6 was inhibited strongly by FAK/IGF-IR inhibition, and the expression of corresponding genes was inhibited strongly. Inhibition of FAK and IGF-IR lead to low activity of mTOR signal pathway. These data indicated that the activity of FAK may affect the activity of mTOR signal pathway, and FAK signal pathway is possibly the upstream regulatory factor of mTOR signal pathway.
2 The function of mTOR signaling pathway in goat fetal fibroblast and its mechanism
2.1 Cloning of mTOR signaling pathway related genes in Inner Mongolia Cashmere goat and the analysis of their basal expression pattern
In the present study, the 8.6 Kb full length mTOR gene cDNA of Inner Mongolia Cashmere goat was cloned. The partial cDNA segments of S6K1 gene, S6K2 gene, S6 gene and FAK gene were also cloned in the goat. The sequencing analysis was performed and indicated these genes as a highly conserved gene to be very conservative. mTOR gene, S6K1 gene and S6K2 gene were found to be expressed in spleen, kidney, testicle and muscle, showed stronger expression in kidney than in spleen. S6 gene was overexpressed in spleen, testicle and muscle. FAK gene expressed in spleen, testicle and muscle, and expressed thin in testicle. These genes were first cloned and genes expression pattern were first studied in goat, and has laid a bioinformatics foundation for the further study on structure and function.
2.2 The function and mechanism of mTOR signaling pathway on regulation of goat fetal fibroblast growth
Inner Mongolia Cashmere goat fetal fibroblasts (GFb) were treated with CCI-779, a mTOR specific inhibitor. The results indicated that GFb cells were sensitive to CCI-779. CCI-779 inhibits the activity of mTOR signal pathway and cell proliferation, blocks cell cycle, and is cytotoxic to GFb in a dosage dependent manner. GFb cells were treated with CCI-779, cytoskeleton lost normal structure, cell morphology changed. mTOR inhibition leads to the phosphoralation inhibited of S6 while the expression of mTOR、Akt, mTOR, S6kland S6 genes were inhibited. It is possible that CCI-779 can induce apoptosis in GFb cells.
In summary, mTOR signaling pathway was first studied and mTOR gene、S6K1 gene、S6K2 gene、S6 gene and FAK gene were cloned firstly. mTOR signaling pathway was proved to be functional in GFb cells and acts as a key regulator to regulate cell growth. By comparing the experimental results on the mTOR signaling pathway from human cancer cells and goat cells, the possible mechanism of mTOR signaling pathway on the regulation of the cell growth and proliferation may involves the regulation of the phosphorilation of its down targets S6K1 and S6 and the expression of related genes after the mTOR is inhibited.
一、mTOR信号通路在人肿瘤细胞生长调控中的作用与机制
1.人食道癌细胞SEG-1和人正常食道上皮细胞KOB-13中mTOR基因和TSC2基因的克隆与表达检测
mTOR激酶是mTOR信号通路的中心协调器,TSC2是mTOR的上游负调节因子,它们在细胞中的活性与细胞生长调控密切相关。通过RT-PCR从人食道癌细胞SEG-1中和人食道正常上皮细胞KOB-13中分别克隆到了mTOR基因和TSC2基因的cDNA片段并比较了两个基因在两种细胞中的表达情况。结果表明:mTOR基因和TSC2基因在肿瘤细胞SEG-1中高表达。
2.mTOR抑制对SEG-1细胞生长的影响及机制
使用mTOR特异性抑制剂RAD001处理SEG-1细胞,结果显示SEG-1细胞对RAD001敏感。mTOR抑制可引起SEG-1细胞周期阻滞,细胞形态发生改变,抑制细胞增殖甚至导致细胞死亡。mTOR被抑制可强烈抑制其下游靶S6的磷酸化,同时还抑制mTOR、S6K1和S6基因的表达,且这些抑制效应都具有剂量依赖关系。结果表明:RAD001抑制mTOR信号通路的活性,通过抑制mTOR及其下游靶S6的磷酸化和相关基因的表达抑制细胞生长。
3.FAK/IGF-IR与mTOR信号通路的关系
利用FAK和IGF-IR抑制剂TAE226处理人食道癌细胞SEG-1,结果显示SEG-1细胞对TAE226十分敏感。TAE226对SEG-1细胞具有细胞毒性,可使得细胞形态发生明显改变,抑制增殖并可引起细胞死亡,且具有剂量依赖效应。FAK/IGF-IR被抑制,可导致Akt、mTOR、S6K1和S6磷酸化的强烈抑制,同时抑制相应基因的表达。结果表明:TAE226对FAK和IGF-IR的抑制导致了mTOR信号通路活性的强烈抑制,预示FAK可能是mTOR信号通路的调节因子。
二、绒山羊细胞中mTOR信号通路的功能与作用机制
1.内蒙古白绒山羊mTOR信号通路相关蛋白基因的克隆与基本表达模式分析
克隆了内蒙古白绒山羊mTOR基因约8.6Kb的全长cDNA及S6K1、S6K2、S6和FAK基因的部分cDNA片段,序列分析表明几个基因在进化上都是高度保守的。表达模式分析表明mTOR基因、S6K1基因和S6K2基因在脾、肾、睾丸和肌肉中都有表达,在肾中表达稍强,脾中稍弱;S6基因在脾、睾丸和肌肉中都高表达;FAK基因在脾、睾丸和肌肉中都有表达,在睾丸中稍弱一些。这些基因序列和表达模式数据都是首次获得,为开展进一步的研究奠定了基础。
2.mTOR信号通路在绒山羊胎儿成纤维细胞生长调控中的作用与机制
使用mTOR特异性抑制剂CCI-779处理内蒙古白绒山羊胎儿成纤维细胞(GFb),结果表明GFb对CCI-779敏感,CCI-779对GFb具有细胞毒性。CCI-779处理可导致细胞生长抑制,在24小时内引起细胞死亡。mTOR抑制可引起GFb细胞周期阻滞,细胞骨架失去正常组织结构,形态发生明显改变。CCI-779微弱抑制mTOR的磷酸化,强烈抑制S6的磷酸化,同时还抑制mTOR、Akt、S6K1和S6基因的表达,并可引起35KD Caspase-3酶原量减少,且这些抑制均具有剂量依赖效应。结果表明:CCI-779抑制mTOR信号通路的活性,抑制细胞增殖。mTOR被抑制不仅影响其下游S6的磷酸化,而且抑制Akt、S6K1和S6基因的表达,并可能具有诱导绒山羊胎儿成纤维细胞凋亡的作用。
综上所述,本研究首次对mTOR信号通路在绒山羊细胞生长调节中的作用进行研究,克隆了内蒙古白绒山羊mTOR、S6K1、S6K2、S6和FAK基因并研究其基本表达模式,证明了mTOR信号通路存在于绒山羊胎儿成纤维细胞中并调控细胞生长。通过对人肿瘤细胞和内蒙古白绒山羊胎儿成纤维细胞的研究,并将对两种细胞的研究结果进行综合分析,认为mTOR信号通路调控细胞生长的可能机制为:mTOR蛋白激酶被抑制后,通过调节下游靶S6K1和S6的磷酸化及相关基因的表达调控细胞生长。
The mammalian target of rapamycin (mTOR) is a kind of Ser/Thr kinase in mammalian cells. It can recruit and integrate input signals from nutrients, growth factors, energy and environmental stress to regulate cell growth and proliferation via different cellular processes. The mTOR signaling pathway also affects the development of the embryonic stem cells (ESCs) and early embryo, and involved in cancers and metabolism disease. The mTOR signaling pathway has been investigated extensively in human, mouse, rat and cattle, whereas it is not yet studied in goat due to the lack of basic data about genes, gene expression and function. Thus this study uses the human tumor cells as a model to compare with the results from goat to prove that the mTOR signaling pathway plays a critical role in cell proliferation regulation.
1 Function and mechanism of mTOR signaling pathway in regulation of human cancer cells growth
1.1 Cloning and expression of mTOR and TSC2 genes in human esophageal cancer cells and primary normal esophageal epithelial cells
mTOR and TSC2 are two of the most important protein kinases within mTOR signaling pathway related with regulation of cell growth. mTOR is a central regulator in the pathway, and TSC2 works as a negative regulator to mTOR. mTOR cDNA segment and TSC2 cDNA segment were cloned by RT-PCR from human esophageal cancer cells(SEG-1) and primary normal esophageal epithelial cells (KOB-13). The expression of mRNA and proteins between these two kinds of cells were compared by RT-PCR and Western blot, separately. The results showed that the genes overexpressed in SEG-1 cells.
1.2 Effect and mechanism of mTOR inhibition on SEG-1 cells growth
SEG-1 cells were treated with RAD001, a specific inhibitor of mTOR and the results showed that SEG-1 cells are sensitive to RAD001 compared to the control group. RAD001 is cytotoxic to SEG-1 cells, and lead to death of the cells and inhibited cell proliferation. The shape of the cells changed and G1/S cell cycle was arrested by mTOR inhibition. RAD001 weakly inhibited phosphorylation of mTOR, and strongly inhibited phosphorylation of its downstream target S6 while the expression of mTOR、S6K1 and S6 genes were inhibited. The inhibitions depended on dosage of the inhibitor. The results showed that RAD001 inhibits activity of mTOR signal pathway. mTOR inhibition induces mTOR and S6 phosphorylation inhibited, and inhibits the expression of the genes.
1.3 The relationship between the FAK/IGF-IR and the mTOR signaling pathway
TAE266, a dual inhibitor for FAK and IGF-IR, was used to treat SEG-1 cells. SEG-1 cells were sensitive to TAE266 and TAE226 had lethal function to SEG-1 cells. The cells shape was changed distinctly and cell proliferation was inhibited by the inhibitor with dose-dependant effect. The phosphorylation of mTOR, Akt and S6 was inhibited strongly by FAK/IGF-IR inhibition, and the expression of corresponding genes was inhibited strongly. Inhibition of FAK and IGF-IR lead to low activity of mTOR signal pathway. These data indicated that the activity of FAK may affect the activity of mTOR signal pathway, and FAK signal pathway is possibly the upstream regulatory factor of mTOR signal pathway.
2 The function of mTOR signaling pathway in goat fetal fibroblast and its mechanism
2.1 Cloning of mTOR signaling pathway related genes in Inner Mongolia Cashmere goat and the analysis of their basal expression pattern
In the present study, the 8.6 Kb full length mTOR gene cDNA of Inner Mongolia Cashmere goat was cloned. The partial cDNA segments of S6K1 gene, S6K2 gene, S6 gene and FAK gene were also cloned in the goat. The sequencing analysis was performed and indicated these genes as a highly conserved gene to be very conservative. mTOR gene, S6K1 gene and S6K2 gene were found to be expressed in spleen, kidney, testicle and muscle, showed stronger expression in kidney than in spleen. S6 gene was overexpressed in spleen, testicle and muscle. FAK gene expressed in spleen, testicle and muscle, and expressed thin in testicle. These genes were first cloned and genes expression pattern were first studied in goat, and has laid a bioinformatics foundation for the further study on structure and function.
2.2 The function and mechanism of mTOR signaling pathway on regulation of goat fetal fibroblast growth
Inner Mongolia Cashmere goat fetal fibroblasts (GFb) were treated with CCI-779, a mTOR specific inhibitor. The results indicated that GFb cells were sensitive to CCI-779. CCI-779 inhibits the activity of mTOR signal pathway and cell proliferation, blocks cell cycle, and is cytotoxic to GFb in a dosage dependent manner. GFb cells were treated with CCI-779, cytoskeleton lost normal structure, cell morphology changed. mTOR inhibition leads to the phosphoralation inhibited of S6 while the expression of mTOR、Akt, mTOR, S6kland S6 genes were inhibited. It is possible that CCI-779 can induce apoptosis in GFb cells.
In summary, mTOR signaling pathway was first studied and mTOR gene、S6K1 gene、S6K2 gene、S6 gene and FAK gene were cloned firstly. mTOR signaling pathway was proved to be functional in GFb cells and acts as a key regulator to regulate cell growth. By comparing the experimental results on the mTOR signaling pathway from human cancer cells and goat cells, the possible mechanism of mTOR signaling pathway on the regulation of the cell growth and proliferation may involves the regulation of the phosphorilation of its down targets S6K1 and S6 and the expression of related genes after the mTOR is inhibited.
引文
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