Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function.

摘要: p53 exerts its tumor suppressor function mainly through transcriptional induction of target genes involved in several processes, including cell cycle checkpoints, apoptosis, and regulation redox status. antioxidant is dependent on activity proceeds by sequential proapoptotic targets. However, none the thus far renowned targets have proved able to abolish their own intracellular reactive oxygen species (ROS) accumulation caused deficiency, therefore pointing existence other prominent yet unknown Here, we show that TP53INP1 represents such a target. Indeed, transcript oxidative stress strictly p53. Mouse embryonic fibroblasts (MEF) splenocytes derived from TP53INP1-deficient (inp1 A/A) mice accumulate ROS, whereas overexpression p53-deficient MEFs rescues ROS levels those p53-proficient cells, indicating independent. Furthermore, inp1 A/A cells oxidant challenge associated with decreased expression p21/Cdkn1a, Sesn2, TAp73, Puma, Bax. Mutation Ser 58 (equivalent human 46) abrogates transcription these genes, TP53INP1-mediated phosphorylation implicated this process. In addition, deficiency results an (N-acetylcysteine)-sensitive acceleration proliferation. Finally, increases stress–related lymphoma incidence decreases survival +/A mice. conclusion, our data major actor p53-driven response possesses both p53-independent regulatory p53-dependent function. [Cancer Res 2009;69(1):219–26]