Restricted accessResearch articleFirst published online 2011-09
Absence of Tumor Suppressor Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) Sensitizes Mouse Thymocytes and Embryonic Fibroblasts to Redox-Driven Apoptosis
The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury. Antioxid. Redox Signal. 15, 1639–1653.
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References
1.
AndersonME. Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol, 113:548–555. 1985.
2.
AshwellJD, LuFW, VacchioMS. Glucocorticoids in T cell development and function. Annu Rev Immunol, 18:309–345. 2000.
3.
BarbatiS, ClémentJL, FréjavilleC, BouteillerJC, TordoP, MichelJC, YadanJC. 31P-labeled pyrroline N-oxides: Synthesis of 5-diethylphosphone-5-methyl-1-pyrroline N-oxide (DEPMPO) by oxidation of diethyl (2-methylpyrrolidin-2-yl)phosphonate. Synthesis, 2036–2040. 1999.
4.
BieriJG, TolliverTJ, CatignaniGL. Simultaneous determination of alpha-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography. Am J Clin Nutr, 32:2143–2149. 1979.
BreenAP, MurphyJA. Reactions of oxyl radicals with DNA. Free Radic Biol Med, 18:1033–1077. 1995.
7.
CanoCE, GommeauxJ, PietriS, CulcasiM, GarciaS, SeuxM, BarelierS, VasseurS, SpotoRP, PebusqueMJ, DusettiNJ, IovannaJL, CarrierA. Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res, 69:219–226. 2009.
8.
CarrierA, NguyenC, VictoreroG, GranjeaudS, RochaD, BernardK, MiazekA, FerrierP, MalissenM, NaquetP, MalissenB, JordanBR. Differential gene expression in CD3epsilon- and RAG1-deficient thymuses: Definition of a set of genes potentially involved in thymocyte maturation. Immunogenetics, 50:255–270. 1999.
ClarkeAR, PurdieCA, HarrisonDJ, MorrisRG, BirdCC, HooperML, WyllieAH. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature, 362:849–852. 1993.
11.
CulcasiM, RockenbauerA, MercierA, ClémentJL, PietriS. The line asymmetry of electron spin resonance spectra as a tool to determine the cis:trans ratio for spin-trapping adducts of chiral pyrrolines N-oxides: The mechanism of formation of hydroxyl radical adducts of EMPO, DEPMPO, and DIPPMPO in the ischemic-reperfused rat liver. Free Radic Biol Med, 40:1524–1538. 2006.
DusettiNJ, TomasiniR, AziziA, BarthetM, VaccaroMI, FiedlerF, DagornJC, IovannaJL. Expression profiling in pancreas during the acute phase of pancreatitis using cDNA microarrays. Biochem Biophys Res Commun, 277:660–667. 2000.
14.
ErlacherM, MichalakEM, KellyPN, LabiV, NiedereggerH, CoultasL, AdamsJM, StrasserA, VillungerA. BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood, 106:4131–4138. 2005.
15.
GironellaM, SeuxM, XieMJ, CanoC, TomasiniR, GommeauxJ, GarciaS, NowakJ, YeungML, JeangKT, ChaixA, FazliL, MotooY, WangQ, RocchiP, RussoA, GleaveM, DagornJC, IovannaJL, CarrierA, PebusqueMJ, DusettiNJ. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA, 104:16170–16175. 2007.
16.
GommeauxJ, CanoC, GarciaS, GironellaM, PietriS, CulcasiM, PebusqueMJ, MalissenB, DusettiN, IovannaJ, CarrierA. Colitis and colitis-associated cancer are exacerbated in mice deficient for tumor protein 53-induced nuclear protein 1. Mol Cell Biol, 27:2215–2228. 2007.
17.
GriffithOW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med, 27:922–935. 1999.
18.
HershkoT, ChaussepiedM, OrenM, GinsbergD. Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ, 12:377–383. 2005.
19.
HogquistKA, BaldwinTA, JamesonSC. Central tolerance: Learning self-control in the thymus. Nat Rev Immunol, 5:772–782. 2005.
20.
JanickeRU, SohnD, Schulze–OsthoffK. The dark side of a tumor suppressor: Anti-apoptotic p53. Cell Death Differ, 15:959–976. 2008.
21.
JiangPH, MotooY, GarciaS, IovannaJL, PebusqueMJ, SawabuN. Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer. World J Gastroenterol, 12:691–696. 2006.
22.
JiangPH, MotooY, IovannaJL, PebusqueMJ, XieMJ, OkadaG, SawabuN. Tumor protein p53-induced nuclear protein 1 (TP53INP1) in spontaneous chronic pancreatitis in the WBN/Kob rat: Drug effects on its expression in the pancreas. J. Pancreas, 5:205–216. 2004.
23.
KleinL, HinterbergerM, WirnsbergerG, KyewskiB. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol, 9:833–844. 2009.
24.
LevineB, KroemerG. Autophagy in the pathogenesis of disease. Cell, 132:27–42. 2008.
25.
LoweSW, SchmittEM, SmithSW, OsborneBA, JacksT. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature, 362:847–849. 1993.
26.
MaedaS, KamataH, LuoJL, LeffertH, KarinM. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell, 121:977–990. 2005.
27.
MartenssonJ, MeisterA. Glutathione deficiency increases hepatic ascorbic acid synthesis in adult mice. Proc Natl Acad Sci USA, 89:11566–11568. 1992.
OmayeST, TurnbullJD, SauberlichHE. Selected methods for the determination of ascorbic acid in animal cells, tissues, and fluids. Methods Enzymol, 62:3–11. 1979.
33.
OpfermanJT. Apoptosis in the development of the immune system. Cell Death Differ, 15:234–242. 2008.
34.
OrreniusS, GogvadzeV, ZhivotovskyB. Mitochondrial oxidative stress: Implications for cell death. Annu Rev Pharmacol Toxicol, 47:143–183. 2007.
35.
PelicanoH, CarneyD, HuangP. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat, 7:97–110. 2004.
36.
PietriS, LiebgottT, FréjavilleC, TordoP, CulcasiM. Nitrone spin traps and their pyrrolidine analogs in myocardial reperfusion injury: Hemodynamic and ESR implications—evidence for a cardioprotective phosphonate effect for 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide in rat hearts. Eur J Biochem, 254:256–265. 1998.
37.
SablinaAA, BudanovAV, IlyinskayaGV, AgapovaLS, KravchenkoJE, ChumakovPM. The antioxidant function of the p53 tumor suppressor. Nat Med, 11:1306–1313. 2005.
38.
Scherz–ShouvalR, ElazarZ. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol, 17:422–427. 2007.
39.
StrasserA, HarrisAW, CoryS. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell, 67:889–899. 1991.
40.
TakahamaY. Journey through the thymus: Stromal guides for T-cell development and selection. Nat Rev Immunol, 6:127–135. 2006.
41.
TasdemirE, Chiara MaiuriM, MorselliE, CriolloA, D'AmelioM, Djavaheri–MergnyM, CecconiF, TavernarakisN, KroemerG. A dual role of p53 in the control of autophagy. Autophagy, 4:810–814. 2008.
42.
TomasiniR, SamirAA, CarrierA, IsnardonD, CecchinelliB, SodduS, MalissenB, DagornJC, IovannaJL, DusettiNJ. TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. J Biol Chem, 278:37722–37729. 2003.
43.
TomasiniR, SamirAA, PebusqueMJ, CalvoEL, TotaroS, DagornJC, DusettiNJ, IovannaJL. P53-dependent expression of the stress-induced protein (SIP)Eur J Cell Biol, 81:294–301. 2002.
44.
TomasiniR, SamirAA, VaccaroMI, PebusqueMJ, DagornJC, IovannaJL, DusettiNJ. Molecular and functional characterization of the stress-induced protein (SIP) gene and its two transcripts generated by alternative splicing. SIP induced by stress and promotes cell death. J Biol Chem, 276:44185–44192. 2001.
45.
TomasiniR, SeuxM, NowakJ, BontempsC, CarrierA, DagornJC, PebusqueMJ, IovannaJL, DusettiNJ. TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. Oncogene, 24:8093–8104. 2005.
YoshidaK, LiuH, MikiY. Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage. J Biol Chem, 281:5734–5740. 2006.
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