The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells.
The Brn-3a POU family transcription factor is able to induce the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53 expression. Thus, in co-transfection experiments, Brn-3a activates the p53 promoter acting via a region from +22 to +67, located between the most proximal (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction of Brn-3a expression using anti-sense constructs reduces endogenous p53 expression in human neuroblastoma or cervical carcinoma cell lines growing in vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53 expression. These results suggest the existence of a negative feedback loop in which elevated Brn-3a expression induces the expression of p53 which, in turn, antagonises the anti-apoptotic activity of Brn-3a.
Budhram-Mahadeo
Vishwanie
V
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Morris
Peter
P
Ndisang
Daniel
D
Irshad
Shazia
S
Lozano
Guilermina
G
Pedley
Barbara
B
Latchman
David S
DS
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002294:Carcinoma, Squamous Cell; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma; D011401:Promoter Regions, Genetic; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; C494188:POU4F1 protein, human; C494189:Pou4f1 protein, mouse; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53