Oxidative Stress Induces p53-Mediated Apoptosis in Glia: p53 Transcription-Independent Way to Die

Paolo Bonini, Simona Cicconi, Alessio Cardinale, Cristiana Vitale, Anna Lucia Serafino, Maria Teresa Ciotti, Lionel N J L Marlier

Research output: Contribution to journalArticle

Abstract

Oxidative stress has been implicated in the pathogenesis of stroke, traumatic brain injuries, and neurodegenerative diseases affecting both neuronal and glial cells in the central nervous system (CNS). The tumor suppressor protein p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. We investigated the role of p53 and related molecular mechanisms that support oxidative stress-induced apoptosis in glia. For this purpose, we exposed C6 glioma cells and primary cultures of rat cortical astrocytes to an H2O2-induced oxidative stress protocol followed by a recovery period. We evaluated the effects of pifithrin-α (PF-α), which has been reported to protect neurons from ischemic insult by specifically inhibiting p53 DNA-binding activity. Strikingly, PF-α was unable to prevent oxidative stress-induced astrocyte apoptosis. We demonstrate that p53 is able to mediate an apoptotic response by direct signaling at mitochondria, despite its transcriptional activity. The z-VAD-fmk-sensitive apoptotic response requires a caspase-dependent MDM-2 degradation, leading to p53 mitochondrial targeting accompanied by cytochrome c release and nucleosomal fragmentation.

Original languageEnglish
Pages (from-to)83-95
Number of pages13
JournalJournal of Neuroscience Research
Volume75
Issue number1
DOIs
Publication statusPublished - Jan 1 2004

Keywords

  • Astrocyte
  • C6 glioma
  • Caspase
  • Cytochrome
  • Ischemia
  • MDM2
  • Mitochondria

ASJC Scopus subject areas

  • Neuroscience(all)

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    Bonini, P., Cicconi, S., Cardinale, A., Vitale, C., Serafino, A. L., Ciotti, M. T., & Marlier, L. N. J. L. (2004). Oxidative Stress Induces p53-Mediated Apoptosis in Glia: p53 Transcription-Independent Way to Die. Journal of Neuroscience Research, 75(1), 83-95. https://doi.org/10.1002/jnr.10822