人类癌症相关基因HCL-G1的结构、功能及其调控研究
摘要
癌症是目前人类健康的头号杀手，而肺癌是癌症中发病率最高的癌症。目前已知的肺癌发病机理多是生长因子和生长因子的表面受体发生异常所致，因此，进一步阐明受体下游的调控基因对于阐明肺癌的发生机理和进一步设计药物靶位点都是十分有意义的。
本研究针对在肺癌细胞中一个上调非常明显的靶基因——HCL-G1，研究了G1的基因和蛋白质结构，鉴定其属于一个全新的基因家族，在进化中和其他基因平行进化，高度保守。细胞定位结果显示其蛋白特异性表达在核仁，而拆段的结果则显示其N端的信号肽并不具有单独引导其蛋白质正确定位的功能，并且提示我们G1蛋白的完整性对于其定位具有重要意义。我们检测了G1过表达的Hela细胞的增殖速度，发现G1能够显著促进细胞增殖，这说明G1可能和癌症有关系，流式细胞仪的结果证实了G1促进细胞增殖的作用主要体现在加速G1-S和G2-M转位。而western的结果显示G1的促增殖作用并不是通过调节cyclin家族的蛋白来完成的，这就提示G1很可能是通过另外的方式来调节细胞周期，而已知的方式中，p53-p21-CDK2途径是最为普遍的调节方式。我们运用荧光素酶报告系统分析了几条与细胞增殖有关的信号途径，结果显示，G1的过表达能够显著抑制p53、p21的表达。为了阐明上游调控因子和G1表达的关系，我们运用荧光素酶报告系统分析了G1的启动子区域，发现G1一段长约601bp的启动子序列承载了G1 80％以上的表达活性。在该启动子中，有4个真实的MAPK调控的下游转录因子结合位点，E-BOX、CDE、AP1和ETS分别负责G1的正负调控，而在启动子的前100 bp可能还存在一个以上有待鉴定的抑制位点，MEK1和MEKK以一种复杂的方式精确调控G1的转录，EGF、IGF和TGFβ则通过影响这两个MAPK信号途径中主要的激酶来完成对G1的调控。因为己知的研究显示，p53是细胞增殖、分化和凋亡的一个枢纽，接受来自细胞生长个方面的信号，综合决定细胞的命运，而G1的细胞定位强烈暗示了它和rRNA剪切拼接的关系，因此，我们运用Northern检测了G1对于细胞rRNA的剪切拼接的作用，结果显示G1的表达下调以后，rRNA的剪切过程也受到了相应的抑制。我们运用酵母双杂交的方法鉴定了一个G1的相互作用蛋白，PES1，其在酵母中的同源蛋白也是和G1在酵母中的同源蛋白相互作用，并且二者都定位于核仁，PES1也能够通过调控rRNA的剪切拼接来调控细胞周期。
我们的研究最终阐明了G1的上游调控机制，横向作用蛋白和其功能，并且确定了其通过p53-p21-CDK途径影响细胞周期，这一结果证明在肺癌的发生过程中，G1肯定受到异常的上游生长因子信号的影响而发生表达异常，成为癌症发生的一个中间因素。
Cancer is the most dangerous killer in all the diseases, and lung carcinoma is the most one in all the cancer. So far, the cancerogenic mechanism of lung cancer is not well elucidated. Some growth factors and growth factor receptors have been identified to participate in cancerogenic processes, but the downstream pathways regulated by those growth factor receptors are uncleared. Clarif ing these pathways and genes are essential to understand the cancerogenic process and design medicines.This project is for understanding HCL-G1, which is evidently up-regulated in lung carcinoma cells. G1 belongs to a new gene family, which is highly conserved in most Eukaryotes. We transfected G1-GFP plasmid into Hela cells, and found G1 locating to nucleolus. G1_(N-terminal)-GFP was transfected into Hela cells as the same protocol, but it wasn' t rightly located. The results displayed that G1' s signal peptide in its N-terminal is not enough to get a right location. We examined the growth speed of G1 transfected Hela cells, and found G1 has noticeable plus effect to cell proliferation contrasting to control samples. Flow cytometer results showed that overexpression of G1 promoted G1-S and G2-M transitions. For better understanding the downstream target that G1 regulated, western blot was performed to examine CyclinB\E and CDK2, and CyclinB\E' s expression level weren't distinctly changed. It's likely that G1 regulates in cell-cycle by some other pathways, p53-p21-CDK2 is most understanded so far. We tested some signal pathways related to cell cycle in G1 up-and down-expression Hela cells, and found G1 up-expression down-regulated p53 and p21 level. We identified Gl gene promoter region, and found a 601bp region contributing to G1＞80% expression.
本研究针对在肺癌细胞中一个上调非常明显的靶基因——HCL-G1，研究了G1的基因和蛋白质结构，鉴定其属于一个全新的基因家族，在进化中和其他基因平行进化，高度保守。细胞定位结果显示其蛋白特异性表达在核仁，而拆段的结果则显示其N端的信号肽并不具有单独引导其蛋白质正确定位的功能，并且提示我们G1蛋白的完整性对于其定位具有重要意义。我们检测了G1过表达的Hela细胞的增殖速度，发现G1能够显著促进细胞增殖，这说明G1可能和癌症有关系，流式细胞仪的结果证实了G1促进细胞增殖的作用主要体现在加速G1-S和G2-M转位。而western的结果显示G1的促增殖作用并不是通过调节cyclin家族的蛋白来完成的，这就提示G1很可能是通过另外的方式来调节细胞周期，而已知的方式中，p53-p21-CDK2途径是最为普遍的调节方式。我们运用荧光素酶报告系统分析了几条与细胞增殖有关的信号途径，结果显示，G1的过表达能够显著抑制p53、p21的表达。为了阐明上游调控因子和G1表达的关系，我们运用荧光素酶报告系统分析了G1的启动子区域，发现G1一段长约601bp的启动子序列承载了G1 80％以上的表达活性。在该启动子中，有4个真实的MAPK调控的下游转录因子结合位点，E-BOX、CDE、AP1和ETS分别负责G1的正负调控，而在启动子的前100 bp可能还存在一个以上有待鉴定的抑制位点，MEK1和MEKK以一种复杂的方式精确调控G1的转录，EGF、IGF和TGFβ则通过影响这两个MAPK信号途径中主要的激酶来完成对G1的调控。因为己知的研究显示，p53是细胞增殖、分化和凋亡的一个枢纽，接受来自细胞生长个方面的信号，综合决定细胞的命运，而G1的细胞定位强烈暗示了它和rRNA剪切拼接的关系，因此，我们运用Northern检测了G1对于细胞rRNA的剪切拼接的作用，结果显示G1的表达下调以后，rRNA的剪切过程也受到了相应的抑制。我们运用酵母双杂交的方法鉴定了一个G1的相互作用蛋白，PES1，其在酵母中的同源蛋白也是和G1在酵母中的同源蛋白相互作用，并且二者都定位于核仁，PES1也能够通过调控rRNA的剪切拼接来调控细胞周期。
我们的研究最终阐明了G1的上游调控机制，横向作用蛋白和其功能，并且确定了其通过p53-p21-CDK途径影响细胞周期，这一结果证明在肺癌的发生过程中，G1肯定受到异常的上游生长因子信号的影响而发生表达异常，成为癌症发生的一个中间因素。
Cancer is the most dangerous killer in all the diseases, and lung carcinoma is the most one in all the cancer. So far, the cancerogenic mechanism of lung cancer is not well elucidated. Some growth factors and growth factor receptors have been identified to participate in cancerogenic processes, but the downstream pathways regulated by those growth factor receptors are uncleared. Clarif ing these pathways and genes are essential to understand the cancerogenic process and design medicines.This project is for understanding HCL-G1, which is evidently up-regulated in lung carcinoma cells. G1 belongs to a new gene family, which is highly conserved in most Eukaryotes. We transfected G1-GFP plasmid into Hela cells, and found G1 locating to nucleolus. G1_(N-terminal)-GFP was transfected into Hela cells as the same protocol, but it wasn' t rightly located. The results displayed that G1' s signal peptide in its N-terminal is not enough to get a right location. We examined the growth speed of G1 transfected Hela cells, and found G1 has noticeable plus effect to cell proliferation contrasting to control samples. Flow cytometer results showed that overexpression of G1 promoted G1-S and G2-M transitions. For better understanding the downstream target that G1 regulated, western blot was performed to examine CyclinB\E and CDK2, and CyclinB\E' s expression level weren't distinctly changed. It's likely that G1 regulates in cell-cycle by some other pathways, p53-p21-CDK2 is most understanded so far. We tested some signal pathways related to cell cycle in G1 up-and down-expression Hela cells, and found G1 up-expression down-regulated p53 and p21 level. We identified Gl gene promoter region, and found a 601bp region contributing to G1＞80% expression.
引文
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