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.
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.
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DOI：
10.1093/nar/gkl878
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发表时间：
2006
影响因子：
14.9
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中科院分区：
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Brn-3a 和 Brn-3b 转录因子在神经母细胞瘤细胞中具有相反和拮抗的作用，因为 Brn-3a 与分化相关，而 Brn-3b 增强这些细胞的增殖。在这项研究中，我们证明了像 Brn-3a 一样，Brn-3b 与 p53 存在物理相互作用。然而，尽管 Brn-3a 抑制 p53 介导的 Bax 表达，但与 p53 合作增加 p21cip1/waf1，但本研究表明 Brn-3b 与 p53 的共表达增加了 Bax 启动子的反式激活，但不增加 p21cip1/waf1 的反式激活。因此，Brn-3b 与 p53 共表达导致细胞凋亡增强，这与 Brn-3a 与 p53 共表达时存活和分化增加相反。为了使 Brn-3b 与 Bax 启动子上的 p53 合作，它需要该启动子上 p53 位点侧翼的结合位点。此外，Brn-3b 敲除 (KO) 小鼠的神经元对细胞凋亡具有抵抗力，这与与对照组相比，缺乏 Brn-3b 的神经元中 p53 诱导后 Bax 表达减少相关。因此，Brn-3b 与 p53 相互作用并调节 Bax 表达的能力可能证明了一种重要机制，有助于确定 p53 诱导时细胞的命运。
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.