Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival
Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival
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DOI：
10.1073/pnas.0807735105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Kirshenbaum, Lorrie A.
中科院分区：
文献类型：
--
作者：
Shaw, James;Zhang, Tong;Kirshenbaum, Lorrie A.
转录因子E2 F-1驱动增殖和死亡，但差异调节这些不同作用的机制知之甚少。缺氧诱导死亡因子Bnip 3是E2 F-1的靶基因，是线粒体死亡途径的组成部分。控制Bnip 3基因活性的机制仍然是神秘的。在此，我们表明，转录因子NF-κ B提供了一个分子开关，决定是否E2 F-1信号增殖或死亡的生理条件下。在基础非凋亡条件下，NF-κ B B通过与E2 F-1竞争Bnip 3启动子结合，组成性占据并转录沉默Bnip 3基因的转录。相反，在NF-κ B不存在的情况下，或在缺氧期间当NF-κ B丰度降低时，基础Bnip 3基因转录被E2 F-1与Bnip 3启动子的不受限制的结合激活。在NF-κ B信号传导缺陷的心脏和人胰腺癌细胞中，E2 F-1或视网膜母细胞瘤基因产物过表达的基因敲低废除了基础和缺氧诱导的Bnip 3转录。存活激酶PI 3 K/Akt以依赖于NF-κ B活化的方式抑制细胞中Bnip 3的表达水平。因此，举例来说，我们表明NF-κ B对E2 F-1依赖性Bnip 3表达的转录抑制突出了一种超越E2 F-1肿瘤抑制程序的存活途径。我们的数据可以更根本地解释细胞如何通过选择性抑制E2 F-1依赖性死亡基因转录，避免视网膜母细胞瘤/E2 F-1细胞周期途径下游的凋亡。
The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differentially regulate these divergent actions are poorly understood. The hypoxia-inducible death factor Bnip3 is an E2F-1 target gene and integral component of the intrinsic mitochondrial death pathway. The mechanisms that govern Bnip3 gene activity remain cryptic. Herein we show that the transcription factor NF-kappa B provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. Weshow under basal nonapoptotic conditions that NF-kappa B constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-kappa B, or during hypoxia when NF-kappa B abundance is reduced, basal Bnip3 gene transcription is activated by the unrestricted binding of E2F-1 to the Bnip3 promoter. Genetic knock-down of E2F-1 or retinoblastoma gene product over-expression in cardiac and human pancreatic cancer cells deficient for NF-kappa B signaling abrogated basal and hypoxia-inducible Bnip3 transcription. The survival kinase PI3K/Akt inhibited Bnip3 expression levels in cells in a manner dependent upon NF-kappa B activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1-dependent Bnip3 expression by NF-kappa B highlights a survival pathway that overrides the E2F-1 tumor suppressor program. Our data may explain more fundamentally how cells, by selectively inhibiting E2F-1-dependent death gene transcription, avert apoptosis down-stream of the retinoblastoma/E2F-1 cell cycle pathway.