Neurochemical Research

, Volume 28, Issue 1, pp 15–27 | Cite as

p53-Dependent Cell Death Signaling in Neurons

  • Richard S. Morrison
  • Yoshito Kinoshita
  • Mark D. Johnson
  • Weiqun Guo
  • Gwenn A. Garden


The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to multiple forms of cellular stress. p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from animal models and patients with chronic neurodegenerative diseases. p53 deficiency or p53 inhibition protects neurons from a wide variety of acute toxic insults. Signal transduction pathways associated with p53-induced neuronal cell death are being characterized, suggesting that intervention may prove effective in maintaining neuronal viability and restoring function following neural injury and disease.

Apoptosis cell death neurons/neurodegeneration p53 caspase Bcl-2 family 


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  1. 1.
    Ko, L. J. and Prives, C. 1996. p53: Puzzle and paradigm. Genes Dev. 10:1054–1072.Google Scholar
  2. 2.
    Giaccia, A. J. and Kastan, M. B. 1998. The complexity of p53 modulation: Emerging patterns from divergent signals. Genes Dev. 12:2973–2983.Google Scholar
  3. 3.
    Bates, S. and Vousden, K. H. 1996. p53 in signaling checkpoint arrest or apoptosis. Curr. Opin. Genet. Dev. 6:12–18.Google Scholar
  4. 4.
    Asker, C., Wiman, K. G., and Selivanova, G. 1999. p53-induced apoptosis as a safeguard against cancer. Biochem. Biophys. Res. Commun. 265:1–6.Google Scholar
  5. 5.
    Miyashita, T., Harigai, M., Hanada, M., and Reed, J. C. 1994. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 54:3131–3135.Google Scholar
  6. 6.
    Roperch, J. P., Alvaro, V., Prieur, S., Tuynder, M., Nemani, M., Lethrosne, F., Piouffre, L., Gendron, M. C., Israeli, D., Dausset, J., Oren, M., Amson, R., and Telerman, A. 1998. Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat. Med. 4:835–838.Google Scholar
  7. 7.
    Ding, H. F., McGill, G., Rowan, S., Schmaltz, C., Shimamura, A., and Fisher, D. E. 1998. Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system. J. Biol. Chem. 273:28378–28383.Google Scholar
  8. 8.
    Gottlieb, E. and Oren, M. 1998. p53 facilitates pRb cleavage in IL-3 deprived cells: Novel pro-apoptotic activity of p53. EMBO J. 17:3587–3596.Google Scholar
  9. 9.
    Sakhi, S., Bruce, A., Sun, N., Tocco, G., Baudry, M., and Schreiber, S. S. 1994. p53 induction is associated with neuronal damage in the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 91:7525–7529.Google Scholar
  10. 10.
    Sakhi, S., Sun, N., Wing, L. L., Mehta, P., and Schreiber, S. S. 1996. Nuclear accumulation of p53 protein following kainic acid-induced seizures. Neuroreport. 7:493–496.Google Scholar
  11. 11.
    Tan, Z., Sankar, R., Shin, D., Sun, N., Liu, H., Wasterlain, C. G., and Schreiber, S. S. 2002. Differential induction of p53 in immature and adult rat brain following lithium-pilocarpine status epilepticus. Brain Res. 928:187–193.Google Scholar
  12. 12.
    Qin, Z. H., Chen, R. W., Wang, Y., Nakai, M., Chuang, D. M., and Chase, T. N. 1999. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J. Neurosci. 19:4023–4033.Google Scholar
  13. 13.
    Wang, Y., Qin, Z. H., Nakai, M., Chen, R. W., Chuang, D. M., and Chase, T. N. 1999. Co-stimulation of cyclic-AMP-linked metabotropic glutamate receptors in rat striatum attenuates excitotoxin-induced nuclear factor-kappaB activation and apoptosis. NeuroScience. 94:1153–1162.Google Scholar
  14. 14.
    Nakai, M., Qin, Z. H., Chen, J. F., Wang, Y., and Chase, T. N. 2000. Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J. Neurochem. 74:647–658.Google Scholar
  15. 15.
    Napieralski, J. A., Raghupathi, R., and McIntosh, T. K. 1999. The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Brain Res. Mol. Brain Res. 71:78–86.Google Scholar
  16. 16.
    Muir, J. K., Raghupathi, R., Emery, D. L., Bareyre, F. M., and McIntosh, T. K. 1999. Postinjury magnesium treatment attenuates traumatic brain injury-induced cortical induction of p53 mRNA in rats. Exp. Neurol. 159:584–593.Google Scholar
  17. 17.
    Chopp, M., Li, Y., Zhang, Z. G., and Freytag, S. O. 1992. p53 expression in brain after middle cerebral artery occlusion in the rat. Biochem Biophys Res Commun. 182:1201–1207.Google Scholar
  18. 18.
    Watanabe, H., Ohta, S., Kumon, Y., Sakaki, S., and Sakanaka, M. 1999. Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat. Brain Res. 837:38–45.Google Scholar
  19. 19.
    Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Selkoe, D. J. 1992. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 360:672–674.Google Scholar
  20. 20.
    Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X. D., McKay, D. M., Tintner, R., Frangione, B., and et al. 1992. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 258:126–1299.Google Scholar
  21. 21.
    Busciglio, J., Gabuzda, D. H., Matsudaira, P., and Yankner, B. A. 1993. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc. Natl. Acad. Sci. U.S.A. 90:2092–2096.Google Scholar
  22. 22.
    de la Monte, S. M., Sohn, Y. K., and Wands, J. R. 1997. Correlates of p53-and Fas (CD95)-mediated apoptosis in Alzheimer's disease. J. Neurol. Sci. 152:73–83.Google Scholar
  23. 23.
    de la Monte, S. M., Sohn, Y. K., Ganju, N., and Wands, J. R. 1998. P53-and CD95-associated apoptosis in neurodegenerative diseases. Lab. Invest. 78:401–411.Google Scholar
  24. 24.
    LaFerla, F. M., Hall, C. K., Ngo, L., and Jay, G. 1996. Extra-cellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. J. Clin. Invest. 98:1626–1632.Google Scholar
  25. 25.
    Jiang, Y. H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., and Beaudet, A. L. 1998. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 21:799–811.Google Scholar
  26. 26.
    Sawa, A. 1999. Neuronal cell death in Down's syndrome. J. Neural Transm. Suppl. 57:87–97.Google Scholar
  27. 27.
    Seidl, R., Fang-Kircher, S., Bidmon, B., Cairns, N., and Lubec, G. 1999. Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. Neurosci. Lett. 260:9–12.Google Scholar
  28. 28.
    Martin, L. J. 2000. p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis. Neurobiol. Dis. 7:613–622.Google Scholar
  29. 29.
    Steffan, J. S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y. Z., Gohler, H., Wanker, E. E., Bates, G. P., Housman, D. E., and Thompson, L. M. 2000. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. U.S.A. 97:6763–6768.Google Scholar
  30. 30.
    Uberti, D., Belloni, M., Grilli, M., Spano, P., and Memo, M. 1998. Induction of tumour-suppressor phosphoprotein p53 in the apoptosis of cultured rat cerebellar neurones triggered by excitatory amino acids. Eur. J. Neurosci. 10:246–254.Google Scholar
  31. 31.
    Chen, R. W. and Chuang, D. M. 1999. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression: A prominent role in neuroprotection against exitotoxicity. J. Biol. Chem. 274:6039–6042.Google Scholar
  32. 32.
    Anderson, C. N. G. and Tolkovsky, A. M. 1999. A role for MAPK/ERK in sympathetic neuron survival: Protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J. Neurosci. 19:664–673.Google Scholar
  33. 33.
    Chen, R. W., Saunders, P. A., Wei, H., Li, Z., Seth, P., and Chuang, D. M. 1999. Involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: Evidence that GAPDH is upregulated by p53. J. Neurosci. 19:9654–9662.Google Scholar
  34. 34.
    Jordan, J., Galindo, M. F., Prehn, J. H., Weichselbaum, R. R., Beckett, M., Ghadge, G. D., Roos, R. P., Leiden, J. M., and Miller, R. J. 1997. p53 expression induces apoptosis in hippo-campal pyramidal neuron cultures. J. Neurosci. 17:1397–1405.Google Scholar
  35. 35.
    Morris, E. J., Keramaris, E., Rideout, H. J., Slack, R. S., Dyson, N. J., Stefanis, L., and Park, D. S. 2001. Cyclin-dependent kinases and p53 pathways are activated independently and mediate Bax activation in neurons after DNA damage. J. Neurosci. 21:5017–5026.Google Scholar
  36. 36.
    Frank, K. M., Sharpless, N. E., Gao, Y., Sekiguchi, J. M., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J., DePinho, R. A., and Alt, F. W. 2000. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol. Cell. 5:993–1002.Google Scholar
  37. 37.
    Banasiak, K. J. and Haddad, G. G. 1998. Hypoxia-induced apoptosis: Effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res. 797:295–304.Google Scholar
  38. 38.
    Aloyz, R. S., Bamji, S. X., Pozniak, C. D., Toma, J. G., Atwal, J., Kaplan, D. R., and Miller, F. D. 1998. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J. Cell Biol. 143:1691–1703.Google Scholar
  39. 39.
    Crumrine, R. C., Thomas, A. L., and Morgan, P. F. 1994. Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J. Cereb. Blood Flow Metab. 14:887–891.Google Scholar
  40. 40.
    Johnson, M. D., Xiang, H., London, S., Kinoshita, Y. Knudson, M. Mayberg, M., Korsmeyer, S. J., and Morrison, R. S. 1998. Evidence for involvement of Bax and p53, but not caspases, in radiation-induced cell death of cultured postnatal hippocampal neurons. J. Neurosci. Res. 54:721–733.Google Scholar
  41. 41.
    Wood, K. A. and Youle, R. J. 1995. The role of free radicals and p53 in neuron apoptosis in vivo. J. Neurosci. 15:5851–5857.Google Scholar
  42. 42.
    Enokido, Y., Araki, T., Tanaka, K., Aizawa, S., and Hatanaka, H. 1996. Involvement of p53 in DNA strand break-induced apoptosis in postmitotic CNS neurons. Eur. J. Neurosci. 8: 1812–1821.Google Scholar
  43. 43.
    Herzog, K. H., Chong, M. J., Kapsetaki, M., Morgan, J. I., and McKinnon, P. J. 1998. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science. 280:1089–1091.Google Scholar
  44. 44.
    D'sa-Eipper, C., Leonard, J. R., Putcha, G., Zheng, T. S., Flavell, R. A., Rakic, P., Kuida, K., and Roth, K. A. 2001. DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3. Development. 128:137–146.Google Scholar
  45. 45.
    Morrison, R. S., Wenzel, H. J., Kinoshita, Y., Robbins, C. A., Donehower, L. A., and Schwartzkroin, P. A. 1996. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J. Neurosci. 16:1337–1345.Google Scholar
  46. 46.
    Trimmer, P. A., Smith, T. S., Jung, A. B., and Bennett, J. P., Jr. 1996. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration. 5:233–239.Google Scholar
  47. 47.
    Hirata, H. and Cadet, J. L. 1997. p53-knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies. J. Neurochem. 69:780–790.Google Scholar
  48. 48.
    Sakhi, S., Gilmore, W., Tran, N. D., and Schreiber, S. S. 1996. p53-deficient mice are protected against adrenalectomy-induced apoptosis. Neuroreport. 8:233–235.Google Scholar
  49. 49.
    Martin, L. J., Kaiser, A., Yu, J. W., Natale, J. E., and Al-Abdulla, N. A. 2001. Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax. J. Comp. Neurol. 433:299–311.Google Scholar
  50. 50.
    Enokido, Y., Araki, T., Aizawa, S., and Hatanaka, H. 1996. p53 involves cytosine arabinoside-induced apoptosis in cultured cerebellar granule neurons. Neurosci. Lett. 203:1–4.Google Scholar
  51. 51.
    Araki, T., Enokido, Y., Inamura, N., Aizawa, S., Reed, J. C., and Hatanaka, H. 1998. Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin. Brain Res. 794:239–247.Google Scholar
  52. 52.
    Xiang, H., Kinoshita, Y., Knudson, C. M., Korsmeyer, S. J., Schwartzkroin, P. A., and Morrison, R. S. 1998. Bax involvement in p53-mediated neuronal cell death. J. Neurosci. 18:1363–1373.Google Scholar
  53. 53.
    Zaidi, A. U., D'sa-Eipper, C., Brenner, J., Kuida, K., Zheng, T. S., Flavell, R. A., Rakic, P., and Roth, K. A. 2001. Bcl-X(L)-caspase-9 interactions in the developing nervous system: Evidence for multiple death pathways. J. Neurosci. 21:169–175.Google Scholar
  54. 54.
    Halterman, M. W., Miller, C. C., and Federoff, H. J. 1999. Hypoxia-inducible factor-1 alpha mediates hypoxia-induced delayed neuronal death that involves p53. J. Neurosci. 19:6818–6824.Google Scholar
  55. 55.
    Vogel, K. S. and Parada, L. F. 1998. Sympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibromin. Mol. Cell Neurosci. 11:19–28.Google Scholar
  56. 56.
    Lee, E. Y., Chang, C. Y., Hu, N., Wang, Y. C., Lai, C. C., Herrup, K., Lee, W. H., and Bradley, A. 1992. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 359:288–294.Google Scholar
  57. 57.
    Macleod, K. F., Hu, Y., and Jacks, T. 1996. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO. J. 15:6178–6188.Google Scholar
  58. 58.
    Yeung, M. C., Geertsma, F., Liu, J., and Lau, A. S. 1998. Inhibition of HIV-1 gp120-induced apoptosis in neuroblastoma SK-N-SH cells by an antisense oligodeoxynucleotide against p53. AIDS 12:349–354.Google Scholar
  59. 59.
    Lakkaraju, A., Dubinsky, J. M., Low, W. C., and Rahman, Y. E. 2001. Neurons are protected from excitotoxic death by p53 antisense oligonucleotides delivered in anionic liposomes. J. Biol. Chem. 276:32000–32007.Google Scholar
  60. 60.
    Culmsee, C., Zhu, X., Yu, Q. S., Chan, S. L., Camandola, S., Guo, Z., Greig, N. H., and Mattson, M. P. 2001. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem. 77:220–228.Google Scholar
  61. 61.
    Zhang, Y., McLaughlin, R., Goodyer, C., and LeBlanc, A. 2002. Selective cytotoxicity of intracellular amyloid ta peptide 1-42 through p53 and Bax in cultured primary human neurons. J. Cell Biol. 156:519–529.Google Scholar
  62. 62.
    Shahbazian, M. D., Orr, H. T., and Zoghbi, H. Y. 2001. Reduction of purkinje cell pathology in SCA1 transgenic mice by p53 deletion. Neurobiol. Dis. 8:974–981.Google Scholar
  63. 63.
    Johnson, M. D., Kinoshita, Y., Xiang, H., Ghatan, S., and Morrison, R. S. 1999. Contribution of p53-dependent caspase activation to neuronal cell death declines with neuronal maturation. J. Neurosci. 19:2996–3006.Google Scholar
  64. 64.
    Fortin, A., Cregan, S. P., MacLaurin, J. G., Kushwaha, N., Hickman, E. S., Thompson, C. S., Hakim, A., Albert, P. R., Cecconi, F., Helin, K., Park, D. S., and Slack, R. S. 2001. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J. Cell Biol. 155:207–2016.Google Scholar
  65. 65.
    Mattson, M. P., Gary, D. S., Chan, S. L., and Duan, W. 2001. Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease. Biochem. Soc. Symp. 67:151–162.Google Scholar
  66. 66.
    Kuntz, C. T., Kinoshita, Y., Beal, M. F., Donehower, L. A., and Morrison, R. S. 2000. Absence of p53: No effect in a transgenic mouse model of familial amyotrophic lateral sclerosis. Exp. Neurol. 165:184–190.Google Scholar
  67. 67.
    Prudlo, J., Koenig, J., Graser, J., Burckhardt, E., Mestres, P., Menger, M., and Roemer, K. 2000. Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator. Brain Res. 879:183–187.Google Scholar
  68. 68.
    Jayaraman, J. and Prives, C. 1995. Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus. Cell. 81:1021–1029.Google Scholar
  69. 69.
    Huang, L. C., Clarkin, K. C., and Wahl, G. M. 1996. Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc. Natl. Acad. Sci. U.S.A. 93:4827–4832.Google Scholar
  70. 70.
    Chong, M. J., Murray, M. R., Gosink, E. C., Russell, H. R., Srinivasan, A., Kapsetaki, M., Korsmeyer, S. J., and McKinnon, P. J. 2000. Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 97:889–894.Google Scholar
  71. 71.
    Liu, Z. G., Baskaran, R., Lea-Chou, E. T., Wood, L. D., Chen, Y., Karin, M., and Wang, J. Y. 1996. Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature. 384:273–276.Google Scholar
  72. 72.
    Gibson, S., Widmann, C., and Johnson, G. L. 1999. Differential involvement of MEK kinase 1 (MEKK1) in the induction of apoptosis in response to microtubule-targeted drugs versus DNA damaging agents. J Biol Chem. 274:10916–10922.Google Scholar
  73. 73.
    Fuchs, S. Y., Adler, V., Pincus, M. R., and Ronai, Z. 1998. MEKK1/JNK signaling stabilizes and activates p53. Proc. Natl. Acad. Sci U.S.A. 95:10541–10546.Google Scholar
  74. 74.
    Bulavin, D. V., Saito, S., Hollander, M. C., Sakaguchi, K., Anderson, C. W., Appella, E., and Fornace, A. J., Jr. 1999. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO. J. 18:6845–6854.Google Scholar
  75. 75.
    She, Q. B., Chen, N., and Dong, Z. 2000. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J. Biol. Chem. 275:20444–20449.Google Scholar
  76. 76.
    Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Green-berg, M. E. 1995. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331.Google Scholar
  77. 77.
    Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., and Greenberg, M. E. 1997. Regulation of neuronal survival by the serine-thre-onine protein kinase Akt. Science. 275:661–665.Google Scholar
  78. 78.
    Philpott, K. L., McCarthy, M. J.,Klippel, A., and Rubin, L. L. 1997. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J. Cell Biol. 139:809–815.Google Scholar
  79. 79.
    Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M. E. 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241.Google Scholar
  80. 80.
    Zha, J., Harada, H., Yang, E., Jockel, J., and Korsmeyer, S. J. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 87:619–628.Google Scholar
  81. 81.
    Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N., and Tohyama, M. 2001. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J. Biol. Chem. 276: 5256–5264.Google Scholar
  82. 82.
    Mazzoni, I. E., Said, F. A., Aloyz, R., Miller, F. D., and Kaplan, D. 1999. Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway. J. Neurosci. 19:9716–9727.Google Scholar
  83. 83.
    Deckwerth, T. L., Elliott, J. L., Knudson, C. M., Johnson, E. M., Jr., Snider, W. D., and Korsmeyer, S. J. 1996. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron. 17:401–411.Google Scholar
  84. 84.
    Liu, Y. and Kulesz-Martin M. 2001. p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. Carcinogenesis. 22:851–860.Google Scholar
  85. 85.
    Oda, K., Arakawa, H., Tanaka, T., Matsuda, K., Tanikawa, C., Mori, T., Nishimori, H., Tamai, K., Tokino, T., Nakamura, Y., and Taya, Y. 2000. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 102:849–862.Google Scholar
  86. 86.
    Daily, D., Barzilai, A., Offen, D., Kamsler, A., Melamed, E., and Ziv, I. 1999. The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53. Cell Mol. Neurobiol. 19:261–276.Google Scholar
  87. 87.
    Lee, Y., Chong, M. J., and McKinnon, P. J. 2001. Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status. J. Neurosci. 21:6687–6693.Google Scholar
  88. 88.
    Liu, W., Rong, Y., Baudry, M., and Schreiber, S. S. 1999. Status epilepticus induces p53 sequence-specific DNA binding in mature rat brain. Brain Res. Mol. Brain Res. 63:248–253.Google Scholar
  89. 89.
    Kondo, M., Shibata, T., Kumagai, T., Osawa, T., Shibata, N., Kobayashi, M., Sasaki, S., Iwata, M., Noguchi, N., and Uchida, K. 2002. 15-Deoxy-delta 12,14-prostaglandin J2: The endogenous electrophile that induces neuronal apoptosis. Proc. Natl. Acad. Sci. U.S.A. 99:7367–7372.Google Scholar
  90. 90.
    Ryan, K. M., Ernst, M. K., Rice, N. R., and Vousden, K. H. 2000. Role of NF-kappaB in p53-mediated programmed cell death. Nature. 404:892–897.Google Scholar
  91. 91.
    Nonaka, S. and Chuang, D. M. 1998. Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport. 9:2081–2084.Google Scholar
  92. 92.
    Xu, X., Yang, D., Wyss-Coray, T., Yan, J., Gan, L., Sun, Y., and Mucke, L. 1999. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc. Natl. Acad. Sci. U.S.A. 96:7547–7552.Google Scholar
  93. 93.
    Thornborrow, E. C., Patel, S., Mastropietro, A. E., Schwartzfarb, E. M., and Manfredi, J. J. 2002. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene. 21:990–999.Google Scholar
  94. 94.
    Buckbinder, L., Talbott, R., Velasco-Miguel, S., Takenaka, I., Faha, B., Seizinger, B. R., and Kley, N. 1995. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 377: 646–649.Google Scholar
  95. 95.
    Reinke, V. and Lozano, G. 1997. The p53 targets mdm2 and Fas are not required as mediators of apoptosis in vivo. Oncogene. 15:1527–1534.Google Scholar
  96. 96.
    Kobayashi, T., Ruan, S., Jabbur, J. R., Consoli, U., Clodi, K., Shiku, H., Owen-Schaub, L. B., Andreeff, M., Reed, J. C., and Zhang, W. 1998. Differential p53 phosphorylation and activation of apoptosis-promoting genes Bax and Fas/APO-1 by irradiation and ara-C treatment. Cell Death Differ. 5:584–591.Google Scholar
  97. 97.
    Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., and Vogelstein, B. 1997. A model for p53-induced apoptosis. Nature. 389:300–305.Google Scholar
  98. 98.
    Brodsky, M. H., Nordstrom, W., Tsang, G., Kwan, E., Rubin, G. M., and Abrams, J. M. 2000. Drosophila p53 binds a damage response element at the reaper locus. Cell. 101:103–113.Google Scholar
  99. 99.
    Prisco, M., Hongo, A., Rizzo, M. G., Sacchi, A., and Baserga, R. 1997. The insulin-like growth factor I receptor as a physiologically relevant target of p53 in apoptosis caused by interleukin-3 withdrawal. Mol. Cell Biol. 17:1084–1092.Google Scholar
  100. 100.
    Murphy, M., Hinman, A., and Levine, A. J. 1996. Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Genes Dev. 10:2971–2980.Google Scholar
  101. 101.
    Li, P. F., Dietz, R., and von Harsdorf, R. 1999. p53 regulates mi-tochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO. J. 18:6027–6036.Google Scholar
  102. 102.
    Deckwerth, T. L. and Johnson, E. M., Jr. 1993. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J. Cell Biol. 123:1207–1222.Google Scholar
  103. 103.
    Vayssiere, J. L., Petit, P. X., Risler, Y., and Mignotte, B. 1994. Commitment to apoptosis is associated with changes in mito-chondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40. Proc. Natl. Acad. Sci. U.S.A. 91:11752–11756.Google Scholar
  104. 104.
    Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssiere, J. L., Petit, P. X., and Kroemer, G. 1995. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J. Exp. Med. 181:1661–1672.Google Scholar
  105. 105.
    Petit, P. X., Lecoeur, H., Zorn, E., Dauguet, C., Mignotte, B., and Gougeon, M. L. 1995. Alterations in mitochondrial structure and function are early events of dexamethasone-induced thymocyte apoptosis. J. Cell Biol. 130:157–167.Google Scholar
  106. 106.
    Marchetti, P., Castedo, M., Susin, S. A., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskens, M., and Kroemer, G. 1996. Mitochondrial permeability transition is a central coordinating event of apoptosis. J. Exp. Med. 184:1155–11560.Google Scholar
  107. 107.
    Xiang, J., Chao, D. T., and Korsmeyer, S. J. 1996. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc. Natl. Acad. Sci. U.S.A 93: 14559–14563.Google Scholar
  108. 108.
    Cregan, S. P., MacLaurin, J. G., Craig, C. G., Robertson, G. S., Nicholson, D. W., Park, D. S., and Slack, R. S. 1999. Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J. Neurosci. 19:7860–7869.Google Scholar
  109. 109.
    Ghatan, S., Larner, S., Kinoshita, Y., Hetman, M., Patel, L., Xia, Z., Youle, R. J., and Morrison, R. S. 2000. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. J. Cell Biol. 150:335–347.Google Scholar
  110. 110.
    McGinnis, K. M., Gnegy, M. E., and Wang, K. K. 1999. Endogenous bax translocation in SH-SY5Y human neuroblastoma cells and cerebellar granule neurons undergoing apoptosis. J. Neurochem. 72:1899–1906.Google Scholar
  111. 111.
    Putcha, G. V., Deshmukh, M., and Johnson, E. M., Jr. 1999. BAX translocation is a critical event in neuronal apoptosis: Regulation by neuroprotectants, BCL-2, and caspases. J. Neurosci. 19:7476–7485.Google Scholar
  112. 112.
    Vekrellis, K., McCarthy, M. J., Watson, A., Whitfield, J., Rubin, L. L., and Ham, J. 1997. Bax promotes neuronal cell death and is downregulated during the development of the nervous system. Development. 124:1239–1249.Google Scholar
  113. 113.
    Martinou, I., Missotten, M., Fernandez, P. A., Sadoul, R., and Martinou, J. C. 1998. Bax and Bak proteins require caspase activity to trigger apoptosis in sympathetic neurons. Neuroreport. 9:15–19.Google Scholar
  114. 114.
    Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J. M., Susin, S. A., Vieira, H. L., Prevost, M. C., Xie, Z., Matsuyama, S., Reed, J. C., and Kroemer, G. 1998. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science. 281:2027–2031.Google Scholar
  115. 115.
    Schuler, M., Bossy-Wetzel, E., Goldstein, J. C., Fitzgerald, P., and Green, D. R. 2000. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J. Biol. Chem. 275:7337–7342.Google Scholar
  116. 116.
    Relaix, F., Wei, X., Li, W., Pan, J., Lin, Y., Bowtell, D. D., Sassoon, D. A., and Wu, X. 2000. Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc. Natl. Acad. Sci. U.S.A. 97:2105–2110.Google Scholar
  117. 117.
    Deng, Y. and Wu, X. 2000. Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mito-chondria. Proc. Natl. Acad. Sci. U.S.A 97:12050–12055.Google Scholar
  118. 118.
    Yamaguchi, A., Taniguchi, M., Hori, O., Ogawa, S., Tojo, N., Matsuoka, N., Miyake, S., Kasai, K., Sugimoto, H., Tamatani, M., Yamashita, T., and Tohyama, M. 2002. Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/ hypoxia. J. Biol. Chem. 277:623–629.Google Scholar
  119. 119.
    Attardi, L. D., Reczek, E. E., Cosmas, C., Demicco, E. G., McCurrach, M. E., Lowe, S. W., and Jacks, T. 2000. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 14:704–718.Google Scholar
  120. 120.
    Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T., and Tanaka, N. 2000. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 288:1053–1058.Google Scholar
  121. 121.
    Ferri, K. F. and Kroemer, G. 2001. Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 3:E255–E263.Google Scholar
  122. 122.
    Okamura, S., Arakawa, H., Tanaka, T., Nakanishi, H., Ng, C. C., Taya, Y., Monden, M., and Nakamura, Y. 2001. p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol. Cell. 8:85–94.Google Scholar
  123. 123.
    Levine, A. J. 1997. p53, the cellular gatekeeper for growth and division. Cell. 88:323–331.Google Scholar
  124. 124.
    Prives, C. and Hall, P. A. 1999. The p53 pathway. J. Pathol. 187:112–126.Google Scholar
  125. 125.
    Yu, J., Zhang, L., Hwang, P. M., Rago, C., Kinzler, K. W., and Vogelstein, B. 1999. Identification and classification of p53-regulated genes. Proc. Natl. Acad. Sci. U.S.A. 96:14517–14522.Google Scholar
  126. 126.
    Wang, L., Wu, Q., Qiu, P., Mirza, A., McGuirk, M., Kirschmeier, P., Greene, J. R., Wang, Y., Pickett, C. B., and Liu, S. 2001. Analyses of p53 target genes in the human genome by bioinfor-matic and microarray approaches. J. Biol. Chem. 276:43604–43610.Google Scholar
  127. 127.
    Levrero, M., De Laurenzi, V., Costanzo, A., Gong, J., Wang, J. Y., and Melino, G. 2000. The p53/p63/p73 family of transcription factors: Overlapping and distinct functions. J. Cell Sci. 113:1661–1670.Google Scholar
  128. 128.
    Lohrum, M. A. and Vousden, K. H. 2000. Regulation and function of the p53-related proteins: Same family, different rules. Trends Cell Biol. 10:197–202.Google Scholar
  129. 129.
    Pozniak, C. D., Radinovic, S., Yang, A., McKeon, F., Kaplan, D. R., and Miller, F. D. 2000. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science. 289:304–306.Google Scholar
  130. 130.
    Schreiber, S. S., Sakhi, S., Dugich-Djordjevic, M. M., and Nichols, N. R. 1994. Tumor suppressor p53 induction and DNA damage in hippocampal granule cells after adrenalectomy. Exp. Neurol. 130:368–376.Google Scholar
  131. 131.
    Kitamura, Y., Shimohama, S., Kamoshima, W., Matsuoka, Y., Nomura, Y., and Taniguchi, T. 1997. Changes of p53 in the brains of patients with Alzheimer's disease. Biochem. Biophys. Res. Commun. 232:418–421.Google Scholar
  132. 132.
    Kohji, T., Hayashi, M., Shioda, K., Minagawa, M., Morimatsu, Y., Tamagawa, K., and Oda, M. 1998. Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci. Lett. 243:133–136.Google Scholar
  133. 133.
    Li, Y., Chopp, M., Zhang, Z. G., Zaloga, C., Niewenhuis, L., and Gautam, S. 1994. p53-immunoreactive protein and p53 mRNA expression after transient middle cerebral artery occlusion in rats. Stroke. 25:849–855; discussion 855–856.Google Scholar
  134. 134.
    Tomasevic, G., Kamme, F., Stubberod, P., Wieloch, M., and Wieloch, T. 1999. The tumor suppressor p53 and its response gene p21WAF1/Cip1 are not markers of neuronal death following transient global cerebral ischemia. NeuroScience. 90:781–792.Google Scholar
  135. 135.
    Joo, C. K., Choi, J. S., Ko, H. W., Park, K. Y., Sohn, S., Chun, M. H., Oh, Y. J., and Gwag, B. J. 1999. Necrosis and apoptosis after retinal ischemia: involvement of NMDA-mediated excito-toxicity and p53. Invest. Ophthalmol. Vis. Sci. 40:713–720.Google Scholar
  136. 136.
    Manev, H., Kharlamov, A., and Armstrong, D. M. 1994. Photochemical brain injury in rats triggers DNA fragmentation, p53 and HSP72. Neuroreport. 5:2661–2664.Google Scholar
  137. 137.
    Hughes, P. E., Alexi, T., Yoshida, T., Schreiber, S. S., and Knusel, B. 1996. Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes Bax and Gadd-45 in brain areas showing DNA fragmentation. NeuroScience. 74:1143–1160.Google Scholar
  138. 138.
    Kaya, S. S., Mahmood,, A., Li,, Y., Yavuz, E., Goksel, M., and Chopp, M. 1999. Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res. 818:23–33.Google Scholar
  139. 139.
    Blum, D., Wu, Y., Nissou, M. F., Arnaud, S., Alim Louis, B., and Verna, J. M. 1997. p53 and Bax activation in 6-hydroxy-dopamine-induced apoptosis in PC12 cells. Brain Res. 751:139–142.Google Scholar
  140. 140.
    Schauwecker, P. E. and Steward, O. 1997. Genetic determinants of susceptibility to excitotoxic cell death: Implications for gene targeting approaches. Proc. Natl. Acad. Sci. U.S.A. 94: 4103–4108.Google Scholar
  141. 141.
    Xiang, H., Hochman, D. W., Saya, H., Fujiwara, T., Schwartzkroin, P. A., and Morrison, R. S. 1996. Evidence for p53-mediated modulation of neuronal viability. J. Neurosci. 16:6753–6765.Google Scholar
  142. 142.
    Sadoul, R., Quiquerez, A. L., Martinou, I., Fernandez, P. A., and Martinou, J. C. 1996. p53 protein in sympathetic neurons: Cytoplasmic localization and no apparent function in apoptosis. J. Neurosci. Res. 43:594–601.Google Scholar
  143. 143.
    Davies, A. M. and Rosenthal, A. 1994. Neurons from mouse embryos with a null mutation in the tumour suppressor gene p53 undergo normal cell death in the absence of neurotrophins. Neurosci. Lett. 182:112–114.Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Richard S. Morrison
    • 1
  • Yoshito Kinoshita
    • 1
  • Mark D. Johnson
    • 1
  • Weiqun Guo
    • 1
  • Gwenn A. Garden
    • 1
  1. 1.Department of Neurological Surgery and Department of NeurologyUniversity of Washington School of Medicine, SeattleWashington

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