EXCITOTOXIC LESION OF RAT-BRAIN WITH QUINOLINIC ACID INDUCES EXPRESSION OF P53 MESSENGER-RNA AND PROTEIN AND P53-INDUCIBLE GENES BAX AND GADD-45 IN BRAIN-AREAS SHOWING DNA FRAGMENTATION

Several recent studies have demonstrated that expression of the tumour -suppressor gene p53 increases within the nervous system after injury. In various cell lines wild-type-p53, induced by DNA damage, has been shown to function to halt cell-cycle progression and under certain cir cumstances to induce programmed-cell death or apoptosis. Since wild ty pe-p53 can act as a transcription factor to regulate the expression of p53-responsive genes it is possible that either, or both, functions o f p53 are mediated by down-stream effector genes. However wild-type-p5 3 only weakly activates transcription and it remains to be determined whether p53-responsive genes are expressed in lesioned brain. Here we report that excitotoxic lesion of rat brain with the N-methyl-D-aspart ate receptor agonist, quinolinic acid, induces expression of p53 messe nger RNA and protein in brain regions showing delayed DNA fragmentatio n and that expression of p53 messenger RNA precedes DNA damage detecte d by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick e nd-labelling. In addition, using in situ hybridization and immunocytoc hemistry we demonstrate increased expression of the p53-responsive gen e Gadd-45 (preceding p53 expression) and re-expression of the p53-resp onsive gene Bax (following p53 expression), in these same areas. Bax h as been shown to promote neuronal death by interacting with Bcl-2 fami ly members while Gadd-45 expression has been associated with suppressi on of the cell-cycle and DNA repair. These results suggest that p53 pr otein may function as an active transcription factor in lesioned brain perhaps initiating the re-expression of Bax in injured brain regions. However since Gadd-45 precedes p53 expression it appears unlikely tha t p53 is involved in regulating the early expression of Gadd-45. Taken together however, these results suggest that p53, Bax and Gadd-45 may play important roles in the response (damage/recovery) of the brain f ollowing excitotoxic injury. Copyright (C) 1996 IBRO. Published by Els evier Science Ltd.