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

Joel N. Glasgow, Jing Xin Qiu, David Rassin, Marjorie Grafe, Tom Wood, J. Regino Perez-Polo

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Signal transduction pathways that mediate neuronal commitment to apoptosis involve the nuclear factor kappa B (NF-κB) 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-κB) DNA binding sites clustered upstream of the brain-specific transcription start site in the upstream promoter region of murine bcl-x. Recombinant NF-κB proteins bind to these sites. Also NF-κB 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-κB in support of the hypothesis that NF-κB can act to enhance Bcl-XL expression via highly selective interactions with the bcl-x promoter, where NF-κB binding and promoter activation are dependent on specific DNA binding site sequences and NF-κB protein dimer composition. Hypoxia induces apoptosis in the hippocampus where the NF-κB dimers c-Rel/p50 and p50/p50 bind to the bcl-x promoter NF-κB site.

Original languageEnglish (US)
Article number344958
Pages (from-to)647-659
Number of pages13
JournalNeurochemical Research
Volume26
Issue number6
DOIs
StatePublished - 2001

Keywords

  • Apoptosis
  • Bcl-x
  • Hypoxia
  • NF-κB
  • c-Rel
  • p50

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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