Differential NF-kappa B regulation of bcl-x gene expression in hippocampusand basal forebrain in response to hypoxia

Cell death often occurs after hypoxic/ischemic injury to the central nervou s system. Changes in levels of the anti-apoptotic Bcl-X-L protein may be a determining factor in hypoxia-induced neuronal apoptosis. The transcription factor NF-kappaB regulates bcl-x gene expression. In this study, we examin ed the role of NF-kappaB in the regulation of bcl-x in hypoxia-induced cell death. Rat hippocampus and basal forebrain tissues were collected at diffe rent time points after hypoxia (7%O-2, 93% N-2 for 10 or 20 min). We found that 1) hypoxia induced apoptosis in the hippocampus and basal forebrain; 2 ) the NF-kappaB dimers c-Rel/p50 and p50/p50 bound to the bcl-x promoter NF -kappaB sequence (CS4) in the hippocampus, but only p50/p50 bound to the CS 4 sequence in the basal forebrain and hypoxia-induced differential binding patterns of c-Rel/p50 and p50/p50 correlated with the bcl-x expression patt ern in the hippocampus; 3) the hypoxiainduced patterns of binding of c-Rel/ p50 to the bcl-x promoter CS4 sequence were different from those to the IgG -kappaB enhancer sequence, whereas those of p50/p50 were similar to both se quences; 4) nuclear protein levels of c-Rel, but not p50, correlated with t he c-Rel/p50 DNA binding patterns to the bcl-x CS4 site; and 5) there were differential responses to hypoxia among the different NF-kappaB protein sub units, These results suggest that there is a tissue-specific regulation of bcl-x gene expression by NF-kappaB in hypoxia-induced cell death in the hip pocampus. The absence of these regulating features in the basal forebrain m ay account for the early appearance of apoptosis in response to hypoxia as compared with that in hippocampus, (C) 2001 Wiley-Liss, Inc.