Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis
Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis
复制标题
DOI：
10.1093/carcin/bgp170
复制
发表时间：
2009-09-01
期刊：
影响因子：
4.7
通讯作者：
Kim, Sunghoon
中科院分区：
文献类型：
--
作者：
Choi, Jin Woo;Um, Jung Yeon;Kim, Sunghoon
氨酰转移核糖核酸（tRNA）合成酶相互作用多功能蛋白（AIMP）2是一种与大分子蛋白质合成机制相关的因子，由9种不同的氨酰-tRNA合成酶和3种非酶因子组成。然而，它被证明是一个多方面的调节器，通过与不同的信号介质的多功能相互作用。例如，它可以通过转化生长因子（TGF）-β介导对DNA损伤和肿瘤坏死因子-α（TNF-α）刺激的促凋亡反应和生长停滞信号。考虑到这些途径与肿瘤发生的控制密切相关，预计AIMP 2将作为一种有效的肿瘤抑制剂，广泛覆盖不同的癌症类型。在这里，我们研究了AIMP 2是否会使用野生型，杂合和纯合AIMP 2细胞对其促凋亡和抗增殖活性产生基因剂量效应，以及AIMP 2是否会使用不同的体内肿瘤模型在预防肿瘤发生中起关键作用。与野生型细胞相比，AIMP 2杂合和纯合细胞对DNA损伤和TNF-α的凋亡反应以及对生长阻滞TGF-β信号的敏感性均以剂量依赖性方式降低。在所有体内致癌实验中，杂合AIMP 2小鼠中AIMP 2水平的降低提供了对肿瘤形成的更高易感性。因此，这项工作证明了AIMP 2在决定细胞增殖和死亡方面的功能意义，以及作为单倍不足的肿瘤抑制因子。
Aminoacyl-transfer ribonucleic acid (tRNA) synthetases-interacting multifunctional protein (AIMP) 2 is a factor associated with the macromolecular protein synthesis machinery consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. However, it was shown to work as a multifaceted regulator through the versatile interactions with diverse signal mediators. For instance, it can mediate pro-apoptotic response to DNA damage and tumor necrosis factor-alpha (TNF-alpha) stimulus and growth-arresting signal by transforming growth factor (TGF)-beta. Considering that these pathways are critically implicated in the control of tumorigenesis, AIMP2 is expected to work as a potent tumor suppressor with broad coverage against different cancer types. Here we investigated whether AIMP2 would give gene dosage effect on its pro-apoptotic and anti-proliferative activities using the wild-type, hetero- and homozygous AIMP2 cells and whether AIMP2 would be critical in preventing tumorigenesis using different in vivo tumor models. Both the apoptotic responses to DNA damage and TNF-alpha and sensitivity to growth arresting TGF-beta signal were reduced in AIMP2 hetero- and homozygous cells compared with the wild-type cells in dose-dependent manner. In all the in vivo carcinogenesis experiments, reduction of AIMP2 level in heterozygous AIMP2 mice provided higher susceptibility to tumor formation. Thus, this work proves the functional significance of AIMP2 in determination of cell proliferation and death, and as a haploinsufficient tumor suppressor.