Tumor Protein 53–Induced Nuclear Protein 1 Is a Major Mediator of p53 Antioxidant Function
| Autor: | Marcel Culcasi, Carla E. Cano, Juan L. Iovanna, Sylvia Pietri, Sarah Barelier, Nelson Dusetti, Julien Gommeaux, Marie-Josèphe Pébusque, Sophie Vasseur, Rose P. Spoto, Mylène Seux, Stéphane Garcia, Alice Carrier |
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| Přispěvatelé: | Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chimie Provence (LCP), Centre National de la Recherche Scientifique (CNRS)-Université de Provence - Aix-Marseille 1-Institut de Chimie du CNRS (INC), Institut National de la Sante´ et de la Recherche Me´dicale, CentreNational de la Recherche Scientifique, Institut National du Cancer, and La LigueNationale Contre le Cancer. C.E. Cano and J. Gommeaux were supported by La LigueNationale Contre le Cancer and the Association pour la Recherche sur le Cancer., CARRIER, Alice, Université de Provence - Aix-Marseille 1-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Lymphoma Transcription Genetic Tumor suppressor gene [SDV]Life Sciences [q-bio] Cell Growth Processes Oxidative phosphorylation Biology medicine.disease_cause Cell Line Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Nuclear protein 030304 developmental biology Mice Knockout 0303 health sciences Cell growth Nuclear Proteins Hydrogen Peroxide Fibroblasts Cell biology [SDV] Life Sciences [q-bio] Oxidative Stress Oncology 030220 oncology & carcinogenesis Cancer research Phosphorylation Tumor Suppressor Protein p53 Reactive Oxygen Species Intracellular Oxidative stress |
| Zdroj: | Cancer Research Cancer Research, American Association for Cancer Research, 2009, 69, pp.219-226. ⟨10.1158/0008-5472.CAN-08-2320⟩ Cancer Research, 2009, 69, pp.219-226. ⟨10.1158/0008-5472.CAN-08-2320⟩ |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-08-2320 |
| Popis: | 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] |
| Databáze: | OpenAIRE |
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