Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2010 Jun 3;26(3):232–240. doi: 10.1007/s12264-010-1111-0

p53-mediated neuronal cell death in ischemic brain injury

p53介导缺血性脑损伤的神经元死亡

Li-Zhi Hong 1, Xiao-Yuan Zhao 1, Hui-Ling Zhang 1,✉
PMCID: PMC5560294  PMID: 20502500

Abstract

p53 is a key modulator of cellular stress responses. It is activated in the ischemic areas of brain, and contributes to neuronal apoptosis. In various stroke models, p53 deficiency or applications of p53 inhibitors can significantly attenuate brain damage. p53-mediated neuronal apoptosis occurs through various molecular mechanisms. The transcriptional pathway is an important mechanism through which p53 induces neuronal apoptosis by up-regulating the expression of its target gene p21WAF, Peg3/Pw1 or p53-up-regulated modulator of apoptosis (PUMA). In addition, p53 disrupts NF-κB binding to p300 and blocks NF-κB-mediated survival signaling. On the other hand, the transcription-independent pathway mechanism is also of great importance. In this pathway, p53 is translocated to mitochondrial and mediates the release of cytochrome c. In both pathways, p53 seems to play a key role in post-ischemic brain damage and has become a therapeutic target against stroke pathology.

Keywords: p53, cerebral ischemia, apoptosis

References

  • [1].Herrmann O., Baumann B., De Lorenzi R., Muhammad S., Zhang W., Kleesiek J., et al. IKK mediates ischemia-induced neuronal death. Nat Med. 2005;11:1322–1329. doi: 10.1038/nm1323. [DOI] [PubMed] [Google Scholar]
  • [2].Harms K., Nozell S., Chen X. The common and distinct target genes of the p53 family transcription factors. Cell Mol Life Sci. 2004;61:822–842. doi: 10.1007/s00018-003-3304-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Harris S.L., Levine A.J. The p53 pathway: positive and negative feed back loops. Oncogene. 2005;24:2899–2908. doi: 10.1038/sj.onc.1208615. [DOI] [PubMed] [Google Scholar]
  • [4].Mashima T., Tsuruo T. Defects of the apoptotic pathway as therapeutic target against cancer. Drug Resist Updat. 2005;8:339–343. doi: 10.1016/j.drup.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • [5].Green D.R., Chipuk J.E. p53 and metabolism: inside the TIGAR. Cell. 2006;126:30–32. doi: 10.1016/j.cell.2006.06.032. [DOI] [PubMed] [Google Scholar]
  • [6].Miyashita T., Reed J.C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80:293–299. doi: 10.1016/0092-8674(95)90513-8. [DOI] [PubMed] [Google Scholar]
  • [7].Oda E., Ohki R., Murasawa H., Nemoto J., Shibue T., Yamashita T., et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000;288:1053–1058. doi: 10.1126/science.288.5468.1053. [DOI] [PubMed] [Google Scholar]
  • [8].Oda K., Arakawa H., Tanaka T., Matsuda K., Tanikawa C., Mori T., et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 2000;102:849–862. doi: 10.1016/S0092-8674(00)00073-8. [DOI] [PubMed] [Google Scholar]
  • [9].Nakano K., Vousden K.H. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001;7:683–694. doi: 10.1016/S1097-2765(01)00214-3. [DOI] [PubMed] [Google Scholar]
  • [10].Yu J., Zhang L., Hwang P.M., Kinzler K.W., Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001;7:673–682. doi: 10.1016/S1097-2765(01)00213-1. [DOI] [PubMed] [Google Scholar]
  • [11].Chipuk J.E., Kuwana T., Bouchier-Hayes L., Droin N.M., Newmeyer D.D., Schuler M., et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303:1010–1014. doi: 10.1126/science.1092734. [DOI] [PubMed] [Google Scholar]
  • [12].Marchenko N.D., Zaika A., Moll U.M. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem. 2000;275:16202–16212. doi: 10.1074/jbc.275.21.16202. [DOI] [PubMed] [Google Scholar]
  • [13].Mihara M., Erster S., Zaika A., Petrenko O., Chittenden T., Pancoska P., et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11:577–590. doi: 10.1016/S1097-2765(03)00050-9. [DOI] [PubMed] [Google Scholar]
  • [14].Erster S., Mihara M., Kim R.H., Petrenko O., Moll U.M. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol. 2004;24:6728–6741. doi: 10.1128/MCB.24.15.6728-6741.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Toledo F., Wahl G.M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–923. doi: 10.1038/nrc2012. [DOI] [PubMed] [Google Scholar]
  • [16].Murray-Zmijewski F., Lane D.P., Bourdon J.C. P53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. 2006;13:962–972. doi: 10.1038/sj.cdd.4401914. [DOI] [PubMed] [Google Scholar]
  • [17].Crumrine R., Thomas A., Morgan P. Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab. 1994;14:887–891. doi: 10.1038/jcbfm.1994.119. [DOI] [PubMed] [Google Scholar]
  • [18].Li Y., Chopp M., Zhang Z.G., Zaloga C., Niewenhuis L., Gautam S. p53-immunoreactive protein and p53 messenger RNA expression after transient middle cerebral artery occlusion in rats. Stroke. 1994;25:849–856. doi: 10.1161/01.str.25.4.849. [DOI] [PubMed] [Google Scholar]
  • [19].McGahan L., Hakim A.M., Robertson G.S. Hippocampal myc and p53 expression following transient global ischemia. Mol Brain Res. 1998;56:133–145. doi: 10.1016/S0169-328X(98)00038-2. [DOI] [PubMed] [Google Scholar]
  • [20].Tomasevic G., Shamloo M., Israeli D., Wieloch T. Activation of p53 and its target genes p21 WAF1/Cip1 and PAG608/Wig-1 in ischemic preconditioning. Mol Brain Res. 1999;70:304–313. doi: 10.1016/S0169-328X(99)00146-1. [DOI] [PubMed] [Google Scholar]
  • [21].Yamaguchi A., Taniguchi M., Hori O., Ogawa S., Tojo N., Matsuoka N., et al. Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/hypoxia. J Biol Chem. 2002;277:623–629. doi: 10.1074/jbc.M107435200. [DOI] [PubMed] [Google Scholar]
  • [22].Culmsee C., Siewe J., Junker V., Retiounskaia M., Schwarz S., Camandola S., et al. Reciprocal inhibition of p53 and nuclear factor-κB transcriptional activities determines cell survival or death in neurons. J Neurosci. 2003;23:8586–8595. doi: 10.1523/JNEUROSCI.23-24-08586.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Saito A., Hayashi T., Okuno S., Nishi T., Chan P.H. Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitinproteasome system during reperfusion after stroke: role of oxidative stress. J Cereb Blood Flow Metab. 2005;25:267–280. doi: 10.1038/sj.jcbfm.9600028. [DOI] [PubMed] [Google Scholar]
  • [24].Yonekura I., Takai K., Asai A., Kawahara N., Kirino T. p53 potentiates hippocampal neuronal death caused by global ischemia. J Cereb Blood Flow Metab. 2006;26:1332–1340. doi: 10.1038/sj.jcbfm.9600293. [DOI] [PubMed] [Google Scholar]
  • [25].Endo H., Kamada H., Nito C., Nishi T., Chan P.H. Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci. 2006;26:7974–7983. doi: 10.1523/JNEUROSCI.0897-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Chen C., Hu Q., Yan J., Yang X., Shi X., Lei J., et al. Early inhibition of HIF-1 alpha with small interfering RNA reduces ischemic-reperfused brain injury in rats. Neurobiol Dis. 2009;33:509–517. doi: 10.1016/j.nbd.2008.12.010. [DOI] [PubMed] [Google Scholar]
  • [27].Banasiak K.J., Haddad G.G. Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res. 1998;797:295–304. doi: 10.1016/S0006-8993(98)00286-8. [DOI] [PubMed] [Google Scholar]
  • [28].Watanabe H., Ohta S., Kumon Y., Sakaki S., Sakanaka M. Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat. Brain Res. 1999;837:38–45. doi: 10.1016/S0006-8993(99)01652-2. [DOI] [PubMed] [Google Scholar]
  • [29].van Lookeren Campagne M., Gill R. Increased expression of cyclin G1 and p21WAF1/CIP1 in neurons following transient forebrain ischemia: comparison with early DNA damage. J Neurosci Res. 1998;53:279–296. doi: 10.1002/(SICI)1097-4547(19980801)53:3<279::AID-JNR2>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  • [30].Cheng T., Liu D., Griffin J.H., Fernandez J.A., Castellino F., Rosen E.D., et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9:338–342. doi: 10.1038/nm826. [DOI] [PubMed] [Google Scholar]
  • [31].Xiang H., Hochman D.W., Saya H., Fujiwara T., Schwartzkroin P.A., Morrison R.S. Evidence for P53-mediated modulation of neuronal viability. J Neurosci. 1996;16:6753–6765. doi: 10.1523/JNEUROSCI.16-21-06753.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Leker R.R., Aharonowiz M., Greig N.H., Ovadia H. The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin α. Exp Neurol. 2004;187:478–486. doi: 10.1016/j.expneurol.2004.01.030. [DOI] [PubMed] [Google Scholar]
  • [33].Wadgaonkar R., Phelps K.M., Haque Z., Williams A.J., Silverman E.S., Collins T. CREB-binding protein is a nuclear integrator of nuclear factor kappaB and p53 signaling. J Biol Chem. 1999;274:1879–1882. doi: 10.1074/jbc.274.4.1879. [DOI] [PubMed] [Google Scholar]
  • [34].Webster G.A., Perkins N.D. Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol. 1999;19:3485–3495. doi: 10.1128/mcb.19.5.3485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Ikeda A., Sun X., Li Y., Zhang Y., Eckner R., Doi T.S., et al. p300/CBP-dependent and -independent transcriptional interference between NF-kappaB RelA and p53. Biochem Biophys Res Commun. 2000;272:375–379. doi: 10.1006/bbrc.2000.2786. [DOI] [PubMed] [Google Scholar]
  • [36].Mattson M.P. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 2000;1:120–129. doi: 10.1038/35040009. [DOI] [PubMed] [Google Scholar]
  • [37].Bui T.N., König H.G., Culmsee C., Bauerbach E., Poppe M., Krieglstein J., et al. p75 neurotrophin receptor is required for constitutive and NGF-induced survival signaling in PC12 cells and rat hippocampal neurones. J Neurochem. 2002;81:594–605. doi: 10.1046/j.1471-4159.2002.00841.x. [DOI] [PubMed] [Google Scholar]
  • [38].Culmsee C., Gerling N., Lehmann M., Nikolova-Karakashian M., Prehn J.H., Mattson M.P., et al. Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. Neuroscience. 2002;115:1089–1108. doi: 10.1016/S0306-4522(02)00539-0. [DOI] [PubMed] [Google Scholar]
  • [39].Niizuma K., Endo H., Nito C., Myer D.J., Chan P.H. Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cerebral ischemia. Stroke. 2009;40:618–625. doi: 10.1161/STROKEAHA.108.524447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Grilli M., Memo M. Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ. 1999;6:22–27. doi: 10.1038/sj.cdd.4400463. [DOI] [PubMed] [Google Scholar]
  • [41].Ryan K.M., Ernst M.K., Rice N.R., Vousden K.H. Role of NF-κB in p53-mediated programmed cell death. Nature. 2000;404:892–897. doi: 10.1038/35009130. [DOI] [PubMed] [Google Scholar]
  • [42].Uberti D., Grilli M., Memo M. Contribution of NF-kappaB and p53 in the glutamate-induced apoptosis. Int J Dev Neurosci. 2000;18:447–454. doi: 10.1016/S0736-5748(00)00018-6. [DOI] [PubMed] [Google Scholar]
  • [43].Cregan S.P., Arbour N.A., MacLaurin J.G., Callaghan S.M., Fortin A., Cheung E.C.C., et al. p53 activation domain 1 is essential for PUMA. J Neurosci. 2004;24:10003–10012. doi: 10.1523/JNEUROSCI.2114-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Chung Y.H., Shin C.M., Kim M.J., Lee E.Y., Kim G., Cha C.I. Enhanced expression of p53 in reactive astrocytes following transient focal ischemia. Neurol Res. 2002;24:324–328. doi: 10.1179/016164102101199828. [DOI] [PubMed] [Google Scholar]
  • [45].Nijboer C.H., Heijnen C.J., Groenendaal F., May M.J., van Bel F., Kavelaars A. A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage. Stroke. 2008;39:2578–2586. doi: 10.1161/STROKEAHA.108.516401. [DOI] [PubMed] [Google Scholar]
  • [46].Zhang X.D., Wang Y., Wang Y., Zhang X., Han R., Wu J.C., et al. p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy. 2009;5:339–350. doi: 10.4161/auto.5.3.8174. [DOI] [PubMed] [Google Scholar]
  • [47].Wang Y., Qin Z.H., Nakai M., Chen R.W., Chuang D.M., Chase T.N. Co-stimulation of cyclic-AMP-linked metabotropic glutamate receptors in rat striatum attenuates excitotoxin-induced nuclear factor-kappaB activation and apoptosis. Neuroscience. 1999;94:1153–1162. doi: 10.1016/S0306-4522(99)00264-X. [DOI] [PubMed] [Google Scholar]
  • [48].Qin Z.H., Chen R.W., Wang Y., Nakai M., Chuang D.M., Chase T.N. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci. 1999;19:4023–4033. doi: 10.1523/JNEUROSCI.19-10-04023.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Nakai M., Qin Z.H., Chen J.F., Wang Y., Chase T.N. Kainic acidinduced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J Neurochem. 2000;74:647–658. doi: 10.1046/j.1471-4159.2000.740647.x. [DOI] [PubMed] [Google Scholar]
  • [50].Cao Y., Gu Z.L., Lin F., Han R., Qin Z.H. Caspase-1 inhibitor Ac-YVAD-CHO attenuates quinolinic acid-induced increases in p53 and apoptosis in rat striatum. Acta Pharmacol Sin. 2005;26:150–154. doi: 10.1111/j.1745-7254.2005.00525.x. [DOI] [PubMed] [Google Scholar]
  • [51].Liang Z.Q., Wang X.X., Wang Y., Chuang D.M., DiFiglia M., Chase T.N., et al. Susceptibility of striatal neurons to excitotoxic injury correlates with basal levels of Bcl-2 and the induction of P53 and c-Myc immunoreactivity. Neurobiol Dis. 2005;20:562–573. doi: 10.1016/j.nbd.2005.04.011. [DOI] [PubMed] [Google Scholar]
  • [52].Liang Z.Q., Li Y.L., Zhao X.L., Han R., Wang X.X., Wang Y., et al. NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Res. 2007;1145:190–203. doi: 10.1016/j.brainres.2007.01.130. [DOI] [PubMed] [Google Scholar]
  • [53].Caelles C., Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994;370:220–223. doi: 10.1038/370220a0. [DOI] [PubMed] [Google Scholar]
  • [54].Haupt Y., Rowan S., Shaulian E., Vousden K.H., Oren M. Induction of apoptosis in HeLa cells by trans-activation-deficient p53. Genes Dev. 1995;9:2170–2183. doi: 10.1101/gad.9.17.2170. [DOI] [PubMed] [Google Scholar]
  • [55].Vaseva A.V., Moll U.M. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009;1787:414–420. doi: 10.1016/j.bbabio.2008.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Ding H.F., McGill G., Rowan S., Schmaltz C., Shimamura A., Fisher D.E. Oncogene dependent regulation of caspase activation by p53 protein in a cell-free system. J Biol Chem. 1998;273:28378–28383. doi: 10.1074/jbc.273.43.28378. [DOI] [PubMed] [Google Scholar]
  • [57].Gottlieb E., Oren M. p53 facilitates pRb cleavage in IL-3-deprived cells: novel proapoptotic activity of p53. EMBO J. 1998;17:3587–3596. doi: 10.1093/emboj/17.13.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Kroemer G., Galluzzi L., Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99–163. doi: 10.1152/physrev.00013.2006. [DOI] [PubMed] [Google Scholar]
  • [59].Endo H., Saito A., Chan P.H. Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischemia. Biochem Soc Trans. 2006;34:1283–1286. doi: 10.1042/BST0341283. [DOI] [PubMed] [Google Scholar]
  • [60].Bonini P., Cicconi S., Cardinale A., Vitale C., Serafino A.L., Ciotti M.T., et al. Oxidative stress induces p53-mediated apoptosis in glia: p53 transcription-independent way to die. J Neurosci Res. 2004;75:83–95. doi: 10.1002/jnr.10822. [DOI] [PubMed] [Google Scholar]
  • [61].Racay P., Tatarkova Z., Drgova A., Kaplan P., Dobrota D. Effect of ischemic preconditioning on mitochondrial dysfunction and mitochondrial p53 translocation after transient global cerebral ischemia in rats. Neurochem Res. 2007;32:1823–1832. doi: 10.1007/s11064-007-9437-3. [DOI] [PubMed] [Google Scholar]
  • [62].Vogelstein B., Lane D.P., Levine A.J. Surfing the p53 network. Nature. 2000;408:307–310. doi: 10.1038/35042675. [DOI] [PubMed] [Google Scholar]
  • [63].Yang L., Tao L.Y., Chen X.P. Roles of NF-kappaB in central nervous system damage and repair. Neurosci Bull. 2007;23:307–313. doi: 10.1007/s12264-007-0046-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES