人类癌症相关基因FoxP4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。目前已知的癌症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癌症的发生机理和进一步设计药物靶位点都是十分有意义的。
forkhead box P4(FoxP4)就是本文作者在利用生物信息学方法筛选人类心脏发育候选基因的过程中发现的一个人类新基因，目前发现三种转录本。该基因编码蛋白属于Fox转录因子家族P亚家族，包含一个N-端C2HC型锌指结构(307aa-332aa)和一个C-端Fork Head(465aa-547aa)结构域，在343aa至366aa有一个Coiled Coil Motif，具有结合DNA的功能。在哺乳动物中，如大鼠、小鼠，发现了它的同源蛋白，并且它们之间具有极高的保守度，说明此蛋白所在的亚家族可能具有一定的功能。组织表达分析表明该基因在80天胚胎中有不同的表达模式，且在大脑、胃、肾和肺组织中有较高水平的表达。亚细胞定位分析表明FoxP4分布于细胞质中，是一种胞浆蛋白。转录活性分析在COS7细胞中过表达FoxP4蛋白可以使MAPK信号途径的下游转录因子SRE的转录激活活性显著提高。此外，过表达FoxP4蛋白对Hela细胞的生长表现出一定的促进作用。综合目前的研究结果来看，FoxP4可能通过MAPK信号途径参与了对细胞生命活动的调控过程。
另外，通过酵母双杂交技术筛出FoxP4蛋白的两种相互作用候选蛋白Cat D和Tcap。Cat D是一个很有效的内源性蛋白质水解酶，很多研究表明它与细胞凋亡有关。如Cat D参与Fas介导的细胞调亡的信号转导，并在P53介导的细胞凋亡中起重要作用，还促使线粒体释放细胞色素c。因此我们推测FoxP4也可能参与了细胞凋亡。另一方面，与Titin相互作用的蛋白Tcap，在心肌伸展机制有非常重要的作用，这也为从其他方面研究FoxP4的功能提供了线索。
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.forkhead box P4 (FoxP4) is one of the candidate genes that the author of this article obtained from the scanning for genes related to heart development with bioinformatics methods. This protein contains a consensus domain of CCHC Zinc finger in N-terminal ( 307aa-332aa ) , a Fork Head(465aa-547aa) domain in C-terminal, and a motif, Coiled Coil, between 343aa to 366aa . In many mammalians, such as mouse, rat, and so on, we discovered the homologues of FoxP4 and they present highly consensus during evolution, which suggests the potential importance of this subfamily. Expression assays present that FoxP4 is expressed with different pattern at fetal of 80 days and strongly expressed in brain, stomach, kidney and lung. The results of transcripteion activity assays show that overexpression of FoxP4 in COS7 cells can remarkably activate the transcriptional activity of SRE, which are downstream effectors of MAPK pathway. Furthermore, overexpression of FoxP4 can slightly promote the growth of Hela cell. In conclusion, we suggest that FoxP4 probably take part in regulation of cell life progress through acting a role in MAPK pathway.
Otherwise, Cat D and rcap, two candidates for interacted with FoxP4, were obtained by screening in Yeast two-hybrid system. Interestingly, Cat D is a potent endoprotease and several studies have linked it to apoptosis. For example, it was shown that Cat D is involved in the signal transduction of Fas-mediated cell death. In addition, Cat D plays a role in p53-mediated cell death and triggers the release of cytochrome c from the mitochondria. Therefore we presume that FoxP4 is involved in apoptosis. In addition a Z disc Tcap , a Titin interacting protein, is a key component of the in vivo cardiomyocyte stretch sensor machinery, and it provide a research clue for us to investigate the function of FoxP4 in other way.
forkhead box P4(FoxP4)就是本文作者在利用生物信息学方法筛选人类心脏发育候选基因的过程中发现的一个人类新基因，目前发现三种转录本。该基因编码蛋白属于Fox转录因子家族P亚家族，包含一个N-端C2HC型锌指结构(307aa-332aa)和一个C-端Fork Head(465aa-547aa)结构域，在343aa至366aa有一个Coiled Coil Motif，具有结合DNA的功能。在哺乳动物中，如大鼠、小鼠，发现了它的同源蛋白，并且它们之间具有极高的保守度，说明此蛋白所在的亚家族可能具有一定的功能。组织表达分析表明该基因在80天胚胎中有不同的表达模式，且在大脑、胃、肾和肺组织中有较高水平的表达。亚细胞定位分析表明FoxP4分布于细胞质中，是一种胞浆蛋白。转录活性分析在COS7细胞中过表达FoxP4蛋白可以使MAPK信号途径的下游转录因子SRE的转录激活活性显著提高。此外，过表达FoxP4蛋白对Hela细胞的生长表现出一定的促进作用。综合目前的研究结果来看，FoxP4可能通过MAPK信号途径参与了对细胞生命活动的调控过程。
另外，通过酵母双杂交技术筛出FoxP4蛋白的两种相互作用候选蛋白Cat D和Tcap。Cat D是一个很有效的内源性蛋白质水解酶，很多研究表明它与细胞凋亡有关。如Cat D参与Fas介导的细胞调亡的信号转导，并在P53介导的细胞凋亡中起重要作用，还促使线粒体释放细胞色素c。因此我们推测FoxP4也可能参与了细胞凋亡。另一方面，与Titin相互作用的蛋白Tcap，在心肌伸展机制有非常重要的作用，这也为从其他方面研究FoxP4的功能提供了线索。
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.forkhead box P4 (FoxP4) is one of the candidate genes that the author of this article obtained from the scanning for genes related to heart development with bioinformatics methods. This protein contains a consensus domain of CCHC Zinc finger in N-terminal ( 307aa-332aa ) , a Fork Head(465aa-547aa) domain in C-terminal, and a motif, Coiled Coil, between 343aa to 366aa . In many mammalians, such as mouse, rat, and so on, we discovered the homologues of FoxP4 and they present highly consensus during evolution, which suggests the potential importance of this subfamily. Expression assays present that FoxP4 is expressed with different pattern at fetal of 80 days and strongly expressed in brain, stomach, kidney and lung. The results of transcripteion activity assays show that overexpression of FoxP4 in COS7 cells can remarkably activate the transcriptional activity of SRE, which are downstream effectors of MAPK pathway. Furthermore, overexpression of FoxP4 can slightly promote the growth of Hela cell. In conclusion, we suggest that FoxP4 probably take part in regulation of cell life progress through acting a role in MAPK pathway.
Otherwise, Cat D and rcap, two candidates for interacted with FoxP4, were obtained by screening in Yeast two-hybrid system. Interestingly, Cat D is a potent endoprotease and several studies have linked it to apoptosis. For example, it was shown that Cat D is involved in the signal transduction of Fas-mediated cell death. In addition, Cat D plays a role in p53-mediated cell death and triggers the release of cytochrome c from the mitochondria. Therefore we presume that FoxP4 is involved in apoptosis. In addition a Z disc Tcap , a Titin interacting protein, is a key component of the in vivo cardiomyocyte stretch sensor machinery, and it provide a research clue for us to investigate the function of FoxP4 in other way.
引文
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