The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1).
We have previously shown that the anti-apoptotic transcription factor, Brn-3a and the pro-apoptotic p53 factor have antagonistic effects on the promoter of the gene encoding the anti-apoptotic Bcl-2 protein, with p53 abolishing activation by Brn-3a. Here we demonstrate that this antagonism is also observed on the gene encoding the pro-apoptotic Bax protein with Brn-3a abolishing the ability of p53 to activate the Bax promoter and induce Bax protein expression. In contrast, Brn-3a and p53 co-operative to induce maximal activation of another p53 target gene encoding the cyclin dependent kinase inhibitor, p21(CIP1/Waf1). These differential effects of Brn-3a on p53-inducible genes involved in apoptosis or growth arrest are paralleled by its effects on these processes themselves. Thus, we show that Brn-3a antagonises the anti-apoptotic effect of p53 but co-operates with p53 to induce cell cycle arrest. The potential role of Brn-3a in determining the outcome of enhanced p53 levels is discussed.
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. v.mahadeo@ich.ucl.ac.uk
Vishwanie
V
Budram-Mahadeo
Peter J
PJ
Morris
David S
DS
Latchman
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005434:Flow Cytometry; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C494188:POU4F1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D008156:Luciferases