The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53

Dvorah Daily, Ari Barzilai*, Daniel Offen, Ariel Kamsler, Eldad Melamed, Ilan Ziv

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)261-276
Number of pages16
JournalCellular and Molecular Neurobiology
Volume19
Issue number2
DOIs
StatePublished - 1999

Funding

FundersFunder number
US–Israel Binational Science Foundation

    Keywords

    • Apoptosis
    • Catecholamines
    • DNA damage
    • Oxidative metabolites
    • P53
    • Parkinson's disease
    • Phosphorylation

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