Identification of a functional antioxidant response element at the HIF1A locus.
Identification of a functional antioxidant response element at the HIF1A locus.
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DOI：
10.1016/j.redox.2018.08.014
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Slattery M
中科院分区：
文献类型：
--
作者：
Lacher SE;Levings DC;Freeman S;Slattery M
活性氧（ROS）是氧化代谢的副产物，在许多生理环境中充当信号分子。然而，如果它们的水平没有严格维持，过量的ROS会导致潜在的细胞毒性氧化应激。因此，几个转录调控网络已经发展到包括高度ROS响应的组件。根据具体情况，这些调控网络可以利用ROS来响应营养条件、代谢或其他生理信号，或响应氧化应激。然而，ROS信号是复杂的，因此各种ROS应答转录因子之间的调控相互作用仍在研究中。在这里，我们表明，转录因子NRF 2，对氧化应激的适应性反应的关键调节因子，直接调节HIF 1A的表达，其编码HIF 1 α，对缺氧的适应性反应的关键转录调节因子。我们使用整合基因组学方法来鉴定HIF 1A作为ROS应答转录物，并且我们在HIF 1A上游约30个酶中发现了NRF 2结合的抗氧化应答元件（ARE）。这个ARE序列是高度保守的，我们证实它直接被NRF 2结合和激活。此外，我们发现HIF 1A在具有高NRF 2活性的乳腺和膀胱肿瘤中上调。总之，我们的研究结果表明，NRF 2的目标是在HIF 1A基因座的功能ARE，并揭示了两个重要的氧响应转录因子之间的直接调节连接。HIF 1A转录是由氧化应激诱导的。NRF 2与HIF 1A上游的抗氧化反应元件（ARE）~ 32激酶结合。调节输出在HIF 1A的ARE上游增加氧化应激。NRF 2激活与选定癌症类型中的HIF 1A上调相关。
Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or other physiological signals, or to respond to oxidative stress. However, ROS signaling is complex, so regulatory interactions between various ROS-responsive transcription factors are still being mapped out. Here we show that the transcription factor NRF2, a key regulator of the adaptive response to oxidative stress, directly regulates expression of HIF1A, which encodes HIF1α, a key transcriptional regulator of the adaptive response to hypoxia. We used an integrative genomics approach to identify HIF1A as a ROS-responsive transcript and we found an NRF2-bound antioxidant response element (ARE) approximately 30 kilobases upstream of HIF1A. This ARE sequence is deeply conserved, and we verified that it is directly bound and activated by NRF2. In addition, we found that HIF1A is upregulated in breast and bladder tumors with high NRF2 activity. Taken together, our results demonstrate that NRF2 targets a functional ARE at the HIF1A locus, and reveal a direct regulatory connection between two important oxygen responsive transcription factors. HIF1A transcription is induced by oxidative stress. NRF2 binds to an antioxidant response element (ARE) ~ 32 kilobases upstream of HIF1A. Regulatory output at the ARE upstream of HIF1A is increased by oxidative stress. NRF2 activation is associated with HIF1A upregulation in select cancer types.
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影响因子：
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