Induction of tumor suppressor p53 and DNA fragmentation in organotypic hippocampal cultures following excitotoxin treatment.
The p53 tumor suppressor gene encodes a cell cycle regulatory protein that is induced by DNA damage and has been implicated in apoptosis. To investigate whether excitotoxic cell death due to kainic acid (KA) and cell death due to N-methyl-D-aspartate (NMDA) share similar molecular mechanisms, we studied p53 expression and DNA fragmentation in organotypic hippocampal slice cultures following excitotoxin treatment. Cellular analyses showed that both p53 induction and DNA fragmentation occurred only in injured neurons following exposure to either excitotoxin. The temporal profiles of these changes demonstrated that p53 induction preceded DNA fragmentation. The extent of regional alterations in p53 expression and DNA fragmentation correlated with drug-related toxicity (i.e., NMDA > KA). These results support the hypothesis that p53 is a marker of neuronal death in the CNS and suggest the possibility that excitotoxin-mediated neuronal death may occur through a p53-dependent pathway.
Sakhi
S
S
Department of Neurology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Bruce
A
A
Sun
N
N
Tocco
G
G
Baudry
M
M
Schreiber
S S
SS
D000818:Animals; D001345:Autoradiography; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology*; D018891:Dentate Gyrus / Q000737:chemistry / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology; D008322:Mammals; D016202:N-Methylaspartate / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D016202:N-Methylaspartate; D007608:Kainic Acid