Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 43
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Molecular Mechanisms Involved in Gas1-Induced Death

J.R. Naranjo and B. Mellström

Centro Nacional de Biotecnología, CSIC, Cantoblanco, Madrid, Spain

We carried out differential screening to identify genes participating in NMDA-induced neuronal death. The Gas1 (growth arrest specific gene 1) gene, whose product is known to inhibit cell cycle progression, was induced in cultured cortico-hippocampal neurons committed to die after a brief exposure to NMDA. Overexpression of Gas1 in cultured hippocampal neurons and in human neuroblastoma NB69 cells produced a marked reduction in the number of viable cells. Furthermore, Gas1 antisense oligodeoxynucleotides or antisense mRNA protected hippocampal neurons or NB69 cells from neuronal death. It is significant that Gas1-induced neuronal death was attenuated by coexpression of the human Bcl-2 protein or the baculoviral caspase inhibitor OpIAP2. While Gas1 does not directly interact with Bcl-2, OpIAP2 co-immunoprecipitates with Gas1. In addition, induction of Gas1 also occurred in rat brain in two models of excitotoxicity: delayed neuronal death after intraperitoneal kainate injection and neuronal death in hippocampal slices after ischemia. These results indicate that Gas1 is induced by activation of glutamate receptors and is part of the gene expression program directing neuronal death after mild excitotoxic insults.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 43
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com