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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Antagonism Of E2f-1 Regulated Bnip3 Transcriptionby Nf-κb Is Essential For Basal Cell Survival
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Antagonism Of E2f-1 Regulated Bnip3 Transcriptionby Nf-κb Is Essential For Basal Cell Survival

机译：Nf-κb对E2f-1调控的Bnip3转录的拮抗作用对基底细胞存活至关重要

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摘要

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 mitochon-drial death pathway. The mechanisms that govern 6nip3 gene activity remain cryptic. Herein we show that the transcription factor NF-κB provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. We show under basal nonapoptotic conditions that NF-κB constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-κB, or during hypoxia when NF-κB 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 reti-noblastoma gene product over-expression in cardiac and human pancreatic cancer cells deficient for NF-κB 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-κB activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1 -dependent Bnip3 expression by NF-κB 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.
机译：转录因子E2F-1驱动增殖和死亡，但对这些差异作用的差异调节机制知之甚少。缺氧诱导性死亡因子Bnip3是E2F-1靶基因，是线粒体内在性死亡内在途径的组成部分。控制6nip3基因活性的机制仍然是秘密的。在本文中，我们表明转录因子NF-κB提供了一种分子开关，该开关决定了E2F-1在生理条件下是增殖还是死亡。我们显示在基础非凋亡条件下，NF-κB通过与E2F-1竞争Bnip3启动子结合而组成性地占据并转录沉默Bnip3基因转录。相反，在不存在NF-κB的情况下，或在缺氧时NF-κB的丰度降低时，基础Bnip3基因转录被E2F-1与Bnip3启动子的不受限制结合所激活。在缺乏NF-κB信号的心脏和人胰腺癌细胞中，E2F-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低氧诱导的Bnip3转录。存活激酶PI3K / Akt依赖于NF-κB活化的方式抑制细胞中Bnip3的表达水平。因此，通过举例的方式，我们显示了NF-κB对E2F-1依赖的Bnip3表达的转录抑制作用突显了覆盖E2F-1肿瘤抑制程序的生存途径。我们的数据可能从根本上解释细胞如何通过选择性抑制E2F-1依赖性死亡基因转录来避免视网膜母细胞瘤/ E2F-1细胞周期途径下游的凋亡。

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