UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate

Hudson, CD; Morris, PJ; Latchman, DS; Budhram-Mahadeo, VS; (2005) Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate. Journal of Biological Chemistry , 280 (12) 11851 - 11858. 10.1074/jbc.M408679200. Gold open access

Abstract

The Brn-3a POU transcription factor is associated with survival and the differentiation of sensory neuronal cells during development. Brn-3a mediates its effects either by the direct regulation of target genes or indirectly upon interaction with proteins such as p53. Brn-3a differentially regulates p53-mediated gene expression and modifies its effect on cell fate. Here we show that, like Bax, Brn-3a antagonizes p53-mediated transcription of another proapoptotic target, Noxa, significantly reducing transactivation of the Noxa promoter by p53. This effect requires the p53 binding site, and electrophoretic mobility shift assay studies suggest that Brn-3a is associated with p53 when it is bound to its site in the Noxa promoter. The wild type but not the mutant promoter can be immunoprecipitated with Brn-3a in chromatin immunoprecipitation assays. Thus, Brn-3a may act by preventing the recruitment of cofactors required for p53 to transactivate this promoter. The co-expression of Brn-3a and p53 results in decreased endogenous Noxa protein in the neuronal cell line, ND7, suggesting a direct functional effect of this interaction. Moreover, there is a significant elevation of both proapoptotic Bax and Noxa proteins in sensory neuronal tissue taken from Brn-3a-/- embryos during development, compared with wild type controls. Striking changes occurred at embryonic day 14.5, a time that precedes a significant loss of specific neurons in the mutant embryos, but not at embryonic day 16.5 when Brn-3a-expressing cells are already lost by apoptosis. Therefore, the lack of antagonism by Brn-3a on activation of proapoptotic p53 target genes may contribute to the increased apoptosis seen in the Brn-3a-/- embryos. These results support a crucial role for Brn-3a in determining the pathway taken by p53 when co-expressed during development and thus in controlling the fate of these cells.

Type: Article
Title: Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate
Location: United States
Open access status: An open access publication
DOI: 10.1074/jbc.M408679200
Publisher version: http://dx.doi.org/10.1074/jbc.M408679200
Language: English
Keywords: Animals, Apoptosis, Binding Sites, Cell Line, Chromatin Immunoprecipitation, DNA, DNA-Binding Proteins, Gene Expression Regulation, Mice, Neurons, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-2, Transcription Factor Brn-3, Transcription Factor Brn-3A, Transcription Factors, Tumor Suppressor Protein p53, bcl-2-Associated X Protein
URI: http://discovery.ucl.ac.uk/id/eprint/36939
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item