Sayan A E, Sayan B S, Gogvadze V, Dinsdale D, Nyman U, Hansen T M, Zhivotovsky B, Cohen G M, Knight R A, Melino G
MRC Toxicology Unit, University of Leicester, Leicester, UK.
Oncogene. 2008 Jul 17;27(31):4363-72. doi: 10.1038/onc.2008.64. Epub 2008 Mar 24.
The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcription-independent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.
p73蛋白是p53家族的成员之一，具有发育和致瘤功能。我们在此表明，在DNA损伤药物和肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体连接引发的细胞凋亡过程中，p73在体外和体内均被caspase-3和-8切割。TAp73及其一些切割产物定位于线粒体。siRNA介导的p73表达下调导致HCT116细胞对TRAIL诱导的细胞凋亡的敏感性发生微小但显著的变化。TAp73的转录缺陷型突变体增强了TRAIL诱导的细胞凋亡，这表明p73蛋白在死亡受体介导的细胞凋亡过程中具有不依赖转录的功能。此外，重组p73蛋白诱导细胞色素c从分离的线粒体中释放，这提供了证据表明非核p73在细胞凋亡进程中可能具有额外的功能。
