Li Xiang, Chen Yuan, Qi Hong, Liu Liyu, Shuai Jianwei
Department of Physics, Xiamen University, Xiamen 361005, China.
Complex Systems Research Center, Shanxi University, Taiyuan 030006, China.
Oncotarget. 2016 Jun 7;7(23):34599-616. doi: 10.18632/oncotarget.8963.
Synonymous mutations, which do not alter the encoded amino acid, have been routinely assumed to be 'neutral' and would have no effect on phenotype or fitness. Yet increasing observations have emerged to overturn this conventional concept. However, convicted elucidation of how synonymous mutations exert biological consequences in oncogenesis is still lacking. By performing systematic analysis of the TNF-α signaling network model, we identify the critical dose which separates the cell survival and apoptosis regions and define the sensitive parameters with single-parameter sensitivity analysis. Combining with the cancer-related mutation spectra obtained from 9 cancers, our results hint that, similar as missense and nonsense mutations, synonymous mutations are also strongly correlated with the parameter sensitivity of the critical dose, providing possible causal mechanism of the mutations in cancer development. Based on such a correlation, we furthermore dissect that members of caspases family proteases (caspase3, 6, 8) could jointly inhibit NFκB activation, providing efficient pro-apoptotic behavior. Thus, we argue that apoptosis module could suppress survival module through negative feedback of caspases family on NFκB.
同义突变不会改变编码的氨基酸，通常被认为是“中性的”，对表型或适应性没有影响。然而，越来越多的观察结果出现，推翻了这一传统观念。然而，对于同义突变如何在肿瘤发生中产生生物学后果，仍缺乏确凿的阐释。通过对TNF-α信号网络模型进行系统分析，我们确定了区分细胞存活和凋亡区域的临界剂量，并通过单参数敏感性分析定义了敏感参数。结合从9种癌症中获得的癌症相关突变谱，我们的结果表明，与错义突变和无义突变类似，同义突变也与临界剂量的参数敏感性密切相关，这为癌症发展中的突变提供了可能的因果机制。基于这种相关性，我们进一步剖析发现，半胱天冬酶家族蛋白酶（caspase3、6、8）的成员可以共同抑制NFκB的激活，从而提供有效的促凋亡行为。因此，我们认为凋亡模块可以通过半胱天冬酶家族对NFκB的负反馈来抑制存活模块。
