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Tumor Protein 53–Induced Nuclear Protein 1 Is a Major Mediator of p53 Antioxidant Function

¹ Institut National de la Santé et de la Recherche Médicale, U624 ‘Stress cellulaire’; ² Aix-Marseille Université, Campus de Luminy; ³ Sondes Moléculaires en Biologie, Laboratoire Chimie Provence UMR 6264, Centre National de la Recherche Scientifique-Universités Aix-Marseille I, II & III, Faculté des Sciences de Saint-Jérôme, Marseille, France

Requests for reprints: Alice Carrier, Institut National de la Sante et de la Recherche Medicale U624, Case 915 Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France. Phone: 33-4-91-82-88-29; Fax: 33-4-91-82-60-83; E-mail: alice.carrier{at}inserm.fr.

Key Words: oxidative stress • reactive oxygen species • electron spin resonance • cell proliferation • tumor suppression

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 Ser⁵⁸ (equivalent to human p53 Ser⁴⁶) abrogates transcription of these genes, indicating that TP53INP1-mediated p53 Ser⁵⁸ 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. [Cancer Res 2009;69(1):219–26]

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