Oxidative stress induces p53-mediated apoptosis in glia: p53 transcription-independent way to die.
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 H(2)O(2)-induced oxidative stress protocol followed by a recovery period. We evaluated the effects of pifithrin-alpha (PF-alpha), which has been reported to protect neurons from ischemic insult by specifically inhibiting p53 DNA-binding activity. Strikingly, PF-alpha 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.
Bonini
Paolo
P
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Cicconi
Simona
S
Cardinale
Alessio
A
Vitale
Cristiana
C
Serafino
Anna Lucia
AL
Ciotti
Maria Teresa
MT
Marlier
Lionel N J-L
LN
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D052160:Benzothiazoles; D015152:Blotting, Northern; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004622:Embryo, Mammalian; D005455:Fluorescent Antibody Technique / Q000379:methods; D019254:Genes, bcl-2 / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins; D009707:Nucleosomes / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D052160:Benzothiazoles; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D009707:Nucleosomes; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014050:Toluene; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C121565:pifithrin; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2