Transcriptional regulation of the BCL-X gene by NF-kappa B is an element of hypoxic responses in the rat brain

Signal transduction pathways that mediate neuronal commitment to apoptosis involve the nuclear factor kappa B (NF-kappaB) transcription factor. The bc l-x gene is a member of the bcl-2 family of genes that regulate apoptosis, and gives rise to two proteins, Bcl-X-L and Bcl-X-S, via alternative mRNA s plicing. Bcl-X-L protein, like Bcl-2, is a dominant inhibitor of apoptotic cell death, whereas Bcl-X-S promotes apoptosis. While there is high express ion of Bcl-X-L in the developing and adult brain, few transcriptional contr ol elements have been identified in the bcl-x promoter. There are two funct ional nuclear factor-kappa B (NF-kappaB) DNA binding sites clustered upstre am of the brain-specific transcription start site in the upstream promoter region of murine bcl-x. Recombinant NF-kappaB proteins bind to these sites. Also NF-kappaB overexpression, coupled with bcl-x promoter/reporter assays using a series of murine bcl-x promoter and deletion mutants, has identifi ed the downstream 1.1kb of the bcl-x promoter as necessary for basal promot er activity and induction by NF-kappaB in support of the hypothesis that NF -kappaB can act to enhance Bcl-X-L expression via highly selective interact ions with the bcl-x promoter, where NF-kappaB binding and promoter activati on are dependent on specific DNA binding site sequences and NF-kappaB prote in dinner composition. Hypoxia induces apoptosis in the hippocampus where t he NF-kappaB dimers c-Rel/p50 and p50/p50 bind to the bcl-x promoter NF-kap paB site.