Cell cycle-related gene expression in the adult rat brain: Selective induction of cyclin G1 and p21 WAF1/CIP1 in neurons following focal cerebral ischemia

Abstract

The present studies were initiated to investigate whether p53 transactivated target genes are induced in a rat model of focal cerebral ischemia. Therefore, we applied in situ hybridization, immunocytochemistry and western blotting to study the temporal and spatial expression of p53 and its transcriptional targets Bax, p21 and cyclin GI following permanent middle cerebral artery occlusion in the rat. Cyclin G1 immunoreactivity was constitutively expressed in the nuclei of cells in the choroid plexus and ependymal cell layer and in the cytoplasm of cell bodies and dendrites of pyramidal neurons of the cerebral cortex. Cyclin G1 messenger RNA and protein levels transiently increased to 150% of contralateral levels in neurons of the ipsilateral frontal and parietal cortex and striatum 3 h following middle cerebral artery occlusion. A low level of constitutively expressed p21 messenger RNA and protein was found in nuclei of cells in the choroid plexus, oligodendrocytes and neurons. p21 messenger RNA and protein levels gradually increased to 250% and 140% of contralateral levels in areas bordering the infarct core up to 6 h following middle cerebral artery occlusion. In contrast, p53 and Bax messenger RNA and protein levels, and protein levels of p27, cyclin-dependent kinase 5, p35 and cyclin E decreased in the infarct core and border areas with time after middle cerebral artery occlusion. The selective up-regulation of cyclin G1 and p21 in neurons in the border zone of a focal ischemic infarct indicates their involvement in an adaptive response to ischemic injury. The possible participation of cyclin G1 and p21 in a signal transduction pathway associated with ischemia-induced cellular stress is discussed.