Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function.
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.
Cano
Carla E
CE
Institut National de la Santé et de la Recherche Médicale, U624 Stress cellulaire, 915 Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France.
Gommeaux
Julien
J
Pietri
Sylvia
S
Culcasi
Marcel
M
Garcia
Stéphane
S
Seux
Mylène
M
Barelier
Sarah
S
Vasseur
Sophie
S
Spoto
Rose P
RP
Pébusque
Marie-Josèphe
MJ
Dusetti
Nelson J
NJ
Iovanna
Juan L
JL
Carrier
Alice
A
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C518507:tumor protein 53-induced nuclear protein 1, mouse; D006861:Hydrogen Peroxide