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

Abstract

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.

Transcriptional Regulation by P53

“…An isoform of p53, p53-b, which can form heterotetramers with wild-type p53, promotes binding to the bax but not the p21 RE (Bourdon et al 2005); conversely, phosphorylation of p53 by c-abl stabilizes the homotetramer, and promotes binding to p21 rather than bax (Wei et al 2005). Brn3a and Brn3b have similarly opposing phenotypes: Brn3a influences p53 to transactivate bax and not p21, whereas Brn3b does the reverse (Budhram-Mahadeo et al 2006).…”

p53 promoter selection: Choosing between life and death

“…The interaction of Brn-3a and Brn-3b with p53 occurs via the POU domain and the DNA binding domain of p53. 27,28 Brn-3a stimulated p53 mediated expression of p21 cip1/waf1 but repressed the expression of Bax. 29,30 On the other hand, co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21 cip1/ waf1 .…”

“…29,30 On the other hand, co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21 cip1/ waf1 . 28 Consequently co-expression of Brn-3b with p53 resulted in enhanced apoptosis, in contrast to the increased survival and differentiation when Brn-3a is co-expressed with p53.…”

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells

“…In the caspase-3/7 screen 30 'hits' had z scores >2 (see ESM Table 2) and were subjected to validation. Of those, 16 (listed in Table 1) were found to be highly validated itself, as well as siRNAs to Tia1 (which encodes an apoptosis-promoting factor) [19], Pou4f2 (which enhances the pro-apoptotic effects of p53) [20] and Lmx1b [21], which regulates the expression of NF-κB target genes, a key element in the induction of beta cell apoptosis [22]. Similarly, Atg4b [23] scored high in the CTB screen.…”