Yan Chunhong, Lu Dan, Hai Tsonwin, Boyd Douglas D
Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
EMBO J. 2005 Jul 6;24(13):2425-35. doi: 10.1038/sj.emboj.7600712. Epub 2005 Jun 2.
Activating transcription factor 3 (ATF3) is rapidly induced by diverse environmental insults including genotoxic stress. We report herein that its interaction with p53, enhanced by genotoxic stress, stabilizes the tumor suppressor thereby augmenting functions of the latter. Overexpression of ATF3 (but not a mutated ATF3 protein (Delta102-139) devoid of its p53-binding region) prevents p53 from MDM2-mediated degradation and leads to increased transcription from p53-regulated promoters. ATF3, but not the Delta102-139 protein, binds the p53 carboxy-terminus and diminishes its ubiquitination and nuclear export. Genotoxic-stressed ATF3-null mouse embryonic fibroblasts, or cells in which ATF3 was reduced by small interference RNA, show inefficient p53 induction and impaired apoptosis compared with wild-type cells. ATF3-null cells (but not wild-type cells), which poorly accumulate p53, are transformed by oncogenic Ras. Thus, ATF3 is a novel stress-activated regulator of p53 protein stability/function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation.
激活转录因子3（ATF3）可被包括基因毒性应激在内的多种环境损伤迅速诱导。我们在此报告，基因毒性应激增强了它与p53的相互作用，从而稳定了肿瘤抑制因子，进而增强了后者的功能。ATF3的过表达（但不包括缺乏p53结合区域的突变型ATF3蛋白（Delta102 - 139））可防止p53被MDM2介导降解，并导致p53调控启动子的转录增加。ATF3而非Delta102 - 139蛋白与p53的羧基末端结合，减少其泛素化和核输出。与野生型细胞相比，基因毒性应激的ATF3基因敲除小鼠胚胎成纤维细胞或通过小干扰RNA降低ATF3表达的细胞，显示出p53诱导效率低下和凋亡受损。ATF3基因敲除细胞（而非野生型细胞）中p53积累不佳，可被致癌性Ras转化。因此，ATF3是一种新型的应激激活的p53蛋白稳定性/功能调节剂，为细胞提供了一种应对广泛环境损伤的方式，从而维持DNA完整性并防止细胞转化。
