Abstract
1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson's disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process.
2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons.
3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a temperature-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactivation dramatically attenuated dopamine toxicity.
4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress.
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REFERENCES
Amson, R. B., et al. (1996). Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: Activation of vertebrate homologues of the Drosophila seven in absentia gene. Proc. Natl. Acad. Sci. USA 93:3953–3957.
Ausubel, F. M., Brent, R., Jingston, R. E., Moore, D. D., Seidman, J. D., Smith, J. A., and Strule, K. (1989). Curr. Prot. Mol. Biol. 1, 3.5.9(a) and 2.2.3 (b), Wiley Interscience, New York.
Basnkian, A. G., and James, S. J. (1994). A rapid and sensitive assay for the detection of DNA fragmentation during early phase of apoptosis. Nucleic Acids Res. 22:2714–2715.
Bates, S., and Vousden, K. H. (1996). p53 in signaling checkpoint arrest or apoptosis. Curr. Opin. Genet. Dev. 6:12–18.
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., and Hannon, G. J. (1995). Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:552–557.
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.
Carle, G. F., Frank. M., and Olson, M. V. (1986). Electrophoretic separation of large DNA molecules by periodic inversion of the electric field. Science 232:65–69.
Deng, C. X., Zhang, P. M., Harper, J. W., Elledge, S. J., and Leder, P. (1995). Mice lacking p21 (C/P/WAF1) undergo normal development, but are defective in G1 checkpoint control. Cell 82:675–684.
D'Mello, S. R., Galli, C., Ciotti, T., and Calissano, P. (1993). Induction of apoptosis in cerebellar granule neurons by low potassium: Inhibition of death by insulin-like growth factor I and cAMP. Proc. Natl. Acad. Sci. USA 90:10989–10993.
Friedlander, P., Haupt, Y., Prives, C., and Oren, M. (1996). A mutant p53 that discriminates between p53-responsive gene cannot induce apoptosis. Mol. Cell. Biol. 16:4961–4971.
Gottlieb, T. M., and Oren, M. (1996). p53 in growth control and neoplasia. Biochim. Biophys. Acta 1287:77–102.
Johnson, N. F., Carpenter, T. R., Jaramillo, R. J., and Liberati, T. A. (1997). DNA damage-inducible genes as biomarkers for exposure to environmental agents. Environ. Health Perspect. 105(Suppl. 4):913–918.
Jordan, J., Galindo, M. F., Prehn, J. H., Weichselbaum, R. R., Beckett, M., Chadge, G. D., Roose, R. P., Leiden, J. M., and Miller, R. J. (1997). p53 expression induced apoptosis in hippocampal pyramidal neuron cultures. J. Neurosci. 17(4):1397–1405.
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.
Ko, L. J., and Prives, C. (1996). p53: Puzzle and paradigm. Genes Dev. 10:1054–1072.
Lasher, R. S., and Zagon, I. S. (1972). The effect of potassium on neuronal differentiation in cultures of dissociated newborn rat cerebellum. Brain Res. 41:482–488.
Lohrum, M., and Scheidtman, K. H. (1996). Differential effects of phosphorylation of rat p53 on transactivation of promoters derived from different p53 responsive genes. Oncogene 13:2527–2539.
Ludwig, R. L., Bates, S., and Vousden, K. H. (1996). Differential activation of target cellular promoter by p53 mutant with impaired apoptosic function. Mol. Cell. Biol. 16:4952–4960.
Miyashita, T., and Reed, J. C. (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299.
Miyashita, T., Krajewski, S., Krajewska, M., Wang, H. G., Lin, H. K., Liebermann, D. A., Hoffman, B., and Reed, J. C. (1994). Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9:1799–1805.
Moldeus, P., Nordenskjold, M., Bolcsfoldi, G., Aiche, A., Haglund, U., and Lambert, B. (1983). Genetic toxicity of dopamine. Mutat. Res. 124:9–23.
Nardi, N., Avidan, G., Daily, D., Zilka-Falb, R., and Barzilai, A. (1997). Biochemical and temporal analysis of events associated with apoptosis induced by lowering the extracellular potassium concentration in mouse cerebellar granule neurons. J. Neurochem. 68:750–759.
Nemani, M., et al. (1996). Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. Proc. Natl. Acad. Sci. USA 93:9039–9042.
Offen, D., Sternin, H., Ziv, I., Melamed, E., and Hochman, A. (1996). Prevention of dopamine-induced apoptosis by antioxidants: Possible implication for treatment of Parkinson's disease. Exp. Neurol. 141:32–39.
Oren, M., and Prives, C. (1996). p53: Upstream, downstream and off stream. Biochim. Biophys. Acta 1288:R13-R19.
Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., and Vogelstein, B. (1997). A model for p53-induced apoptosis. Nature 389:300–305.
Selvakumaran, M., Lin, H. K., Miyashita, T., Wang, H. G., Krajewski, S., Reed, J. C., Hoffman, B., and Liebermann, D. A. (1994). Immediate early up-regulation of bax expression by p53 but not TGF-beta1: A paradigm for distinct apoptotic pathways. Oncogene 9:1791–1798.
Sugrue, M. M., Shin, D. Y., Lee, S. W., and Aaronson, S. A. (1997). Wild type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc. Natl. Acad. Sci.USA 94:9648–9653.
Trimmer, P. A., Smith, T. S., Jung, A. B., and Bennett, J. P., Jr. (1996). Dopamine neurons from transgenic mice with knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 5:233–239.
Waldman, T., Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1996). Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381:713–716.
Wick, M. M. (1989). Levodopa/dopamine analogs as inhibitors of DNA synthesis in human melanoma cells. J. Invest. Dermatol. 92:329S-331S.
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.
Wu, L., and Levine, A. J. (1997). Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: p53-dependent and p53-independent regulation of the mdm2 gene. Mol. Med. 3:441–451.
Yarnold, J. (1997). Molecular aspect to cellular responses to radiotherapy. Radiother. Oncol. 44:1–7.
Yonish-Rouach, E., Resnitzky, D., Lotem, L., Sacks, L., Kimchi, A., and Oren, M. (1991). Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352:345–347.
Yonich-Rouach, E., Grunwald, D., Wilder, S., Kimchi, A., May, E., Lawrence, J., May, P., and Oren, M. (1993). P53-mediated cell death: Relationship to cell cycle control. Mol. Cell. Biol. 13:1415–1423.
Zilkha-Falb, R., Ziv, I., Nardi, N., Offen, D., Melamed, E., and Barzilai, A. (1997). Monoamine-induced apoptotic neuronal cell death. Cell. Mol. Neurobiol. 17(1):101–118.
Ziv, I., Melamed, E., Nardi, N., Luria, D., Achiron, A., Offen, D., and Barzilai, A. (1994). Dopamine induces apoptosis like cell death in cultured chick embryo sympathetic neurons—A possible novel pathogenic mechanism in Parkinson's disease. Neurosci. Lett. 170:136–140.
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Daily, D., Barzilai, A., Offen, D. et al. The Involvement of p53 in Dopamine-Induced Apoptosis of Cerebellar Granule Neurons and Leukemic Cells Overexpressing p53. Cell Mol Neurobiol 19, 261–276 (1999). https://doi.org/10.1023/A:1006933312401
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DOI: https://doi.org/10.1023/A:1006933312401