近日,厦门大学生命科学学院院长林圣彩教授课题组的一项研究表明,存在于细胞内的一种名为Axin的蛋白分子可以通过控制一种名为p53的抑癌基因的活性来决定细胞“命运”。这就意味着,含有过度受损基因组的细胞可以通过二者特定的相互作用促使其“死亡”,从而避免个体发生癌变。这一研究成果刊登在8月23日出版的国际著名学术期刊《自然—细胞生物学》上。
据课题组成员李勤喜副教授介绍,p53是目前人类发现的一种最主要的抑癌基因,有超过一半肿瘤的发生都与p53的基因突变有关。“p53就相当于一名‘分子警察’,在不同的外界刺激下,启动不同的程序,从而抑制癌症的发生。即当DNA受到不可修复的损伤时,p53通过启动让细胞凋亡的程序,促使细胞死亡;当DNA受到损伤比较弱时,p53便启动细胞周期阻滞程序,阻止细胞分裂,再对受损DNA进行修复,从而防止有缺陷的遗传物质传递到子代细胞。”
这名“警察”为什么能够感受到外界不同的刺激从而启动不同的程序?林圣彩课题组经过多年的研究发现,细胞内一种名为Axin的蛋白分子和p53的活动机理有着密切的关系,它可以通过控制p53活性的临界值来决定p53启动何种程序,从而让细胞有不同的“未来”。具体来说,Axin通过形成不同的多蛋白复合体来控制p53的作用方式。
李勤喜说,癌变细胞内的Axin可能发生了突变,功能出现紊乱,不能正常激活p53,导致受损细胞加速繁殖。因此,在未来技术成熟的前提下,也许我们能将正常的Axin导入癌症患者体内,使其恢复调节控制功能,这对于癌症治疗将有重大意义。(生物谷Bioon.com)
生物谷推荐原始出处:
Nature Cell Biology 23 August 2009 | doi:10.1038/ncb1927
Axin determines cell fate by controlling the p53 activation threshold after DNA damage
Qinxi Li1,2, Shuyong Lin1,2, Xuan Wang1,2, Guili Lian1, Zailian Lu1, Huiling Guo1, Ka Ruan1, Yanhai Wang1, Zhiyun Ye1, Jiahuai Han1 & Sheng-Cai Lin1
Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity1, 2, 3, 4, 5, 6. Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2–Axin binding, forming an Axin–Tip60–HIPK2–p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the Axin–Tip60 complex assembly. An axin mutation promotes carcinogenesis in AxinFu/+ (Axin-Fused) mice, consistent with a dominant-negative role for AxinFu in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress.
1 Key Laboratory for Cell Biology and Tumor Cell Engineering of the Ministry of Education, School of Life Sciences, Xiamen University, Fujian 361005, China.
2 These authors contributed equally to this work.