Transcriptional regulation of the BCL-X gene by NF-kappaB 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 bcl-x gene is a member of the bcl-2 family of genes that regulate apoptosis, and gives rise to two proteins, Bcl-XL and Bcl-XS, via alternative mRNA splicing. BCl-XL protein, like Bcl-2, is a dominant inhibitor of apoptotic cell death, whereas Bcl-XS promotes apoptosis. While there is high expression of Bcl-XL in the developing and adult brain, few transcriptional control elements have been identified in the bcl-x promoter. There are two functional nuclear factor-kappa B (NF-kappaB) DNA binding sites clustered upstream 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 identified the downstream 1.1kb of the bcl-x promoter as necessary for basal promoter activity and induction by NF-kappaB in support of the hypothesis that NF-kappaB can act to enhance BCl-XL expression via highly selective interactions with the bcl-x promoter, where NF-kappaB binding and promoter activation are dependent on specific DNA binding site sequences and NF-kappaB protein dimer composition. Hypoxia induces apoptosis in the hippocampus where the NF-kappaB dimers c-Rel/p50 and p50/pS0 bind to the bcl-x promoter NF-kappaB site.
Glasgow
J N
JN
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77555-0652, USA.
Qiu
J
J
Rassin
D
D
Grafe
M
M
Wood
T
T
Perez-Pol
J R
JR
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*; D051020:bcl-X Protein
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein