Nucleic Acids Research Advance Access originally published online on December 1, 2006
Nucleic Acids Research 2006 34(22):6640-6652; doi:10.1093/nar/gkl878
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Nucleic Acids Research, 2006, Vol. 34, No. 22 6640-6652
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression
Medical Molecular Biology Unit, Institute of Child Health, University College London 30 Guilford Street, London WC1N 1EH, UK 1 44 Lincoln's Inns Field, London WC2A 3PX, UK
*To whom correspondence should be addressed. Tel: +44 20 7242 9789 (ext 0761); Fax: +44 20 7905 2301; Email: v.mahadeo{at}ich.ucl.ac.uk
Received August 8, 2006. Revised October 6, 2006. Accepted October 11, 2006.
The Brn-3a and Brn-3b transcription factor have opposite and antagonistic effects in neuroblastoma cells since Brn-3a is associated with differentiation whilst Brn-3b enhances proliferation in these cells. In this study, we demonstrate that like Brn-3a, Brn-3b physically interacts with p53. However, whereas Brn-3a repressed p53 mediated Bax expression but cooperated with p53 to increase p21cip1/waf1, this study demonstrated that co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21cip1/waf1. Consequently co-expression of Brn-3b with p53 resulted in enhanced apoptosis, which is in contrast to the increased survival and differentiation, when Brn-3a is co-expressed with p53. For Brn-3b to cooperate with p53 on the Bax promoter, it requires binding sites that flank p53 sites on this promoter. Furthermore, neurons from Brn-3b knock-out (KO) mice were resistant to apoptosis and this correlated with reduced Bax expression upon induction of p53 in neurons lacking Brn-3b compared with controls. Thus, the ability of Brn-3b to interact with p53 and modulate Bax expression may demonstrate an important mechanism that helps to determine the fate of cells when p53 is induced.
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