Abstract
p53 exerts its tumor suppressor function mainly through transcriptional induction of target genes involved in several processes, including cell cycle checkpoints, apoptosis, and regulation of cell redox status. p53 antioxidant function is dependent on its transcriptional activity and proceeds by sequential induction of antioxidant and proapoptotic targets. However, none of the thus far renowned p53 targets have proved able to abolish on their own the intracellular reactive oxygen species (ROS) accumulation caused by p53 deficiency, therefore pointing to the existence of other prominent and yet unknown p53 antioxidant targets. Here, we show that TP53INP1 represents such a target. Indeed, TP53INP1 transcript induction on oxidative stress is strictly dependent on p53. Mouse embryonic fibroblasts (MEF) and splenocytes derived from TP53INP1-deficient (inp1(-/-)) mice accumulate intracellular ROS, whereas overexpression of TP53INP1 in p53-deficient MEFs rescues ROS levels to those of p53-proficient cells, indicating that TP53INP1 antioxidant function is p53 independent. Furthermore, accumulation of ROS in inp1(-/-) cells on oxidant challenge is associated with decreased expression of p53 targets p21/Cdkn1a, Sesn2, TAp73, Puma, and Bax. Mutation of p53 Ser(58) (equivalent to human p53 Ser(46)) abrogates transcription of these genes, indicating that TP53INP1-mediated p53 Ser(58) phosphorylation is implicated in this process. In addition, TP53INP1 deficiency results in an antioxidant (N-acetylcysteine)-sensitive acceleration of cell proliferation. Finally, TP53INP1 deficiency increases oxidative stress-related lymphoma incidence and decreases survival of p53(+/-) mice. In conclusion, our data show that TP53INP1 is a major actor of p53-driven oxidative stress response that possesses both a p53-independent intracellular ROS regulatory function and a p53-dependent transcription regulatory function.
Highlights
The TP53 gene, which encodes the p53 tumor suppressor, is the most frequently mutated gene in human cancers. p53-dependentNote: Supplementary data for this article are available at Cancer Research Online.C.E
To establish p53 dependence of TP53INP1 expression on oxidative stress, we derived fibroblasts (MEFs) from wt and p53-deficient (p53À/À) embryos, cultured them for 1 hour with or without H2O2, and allowed cells to recover for 12 hours
We show that TP53INP1 is necessary for controlling intracellular reactive oxygen species (ROS) levels both in the absence of exogenous stress and after oxidant challenge, that its induction on oxidative stress is strictly dependent on p53, and that it enhances p53-dependent transcription on oxidative stress
Summary
The TP53 gene, which encodes the p53 tumor suppressor, is the most frequently mutated gene in human cancers. p53-dependentNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).C.E. A good example of this is the recently reported physiologic antioxidant activity of p53, which is dependent on its DNA-binding domain [3]. P53 response to elevated intracellular ROS concentration involves two waves of transcription induction. The first wave starts when cells endure low oxidant concentrations, in which case p53 induces transcription of genes with antioxidant and cell cycle regulatory properties, such as sestrins and p21, to favor the restoration of physiologic intracellular ROS levels [3, 4]. When cells endure long-lasting and/or high concentrations of oxidant, p53 will induce a second wave of transcription of proapoptotic genes, such as those encoding Puma and Bax, to promote cell death [3, 5, 6]. None of the above-mentioned p53 targets induced during the oxidative stress response is capable of fully restoring physiologic ROS levels in the absence of p53, suggesting that a yet unknown p53 target might be responsible for sensing and/or eliminating ROS surplus
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