PALB2 与 KEAP1 相互作用，促进 NRF2 的核积累和功能。
PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function.
机构信息
Department of Radiation Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
出版信息
Mol Cell Biol. 2012 Apr;32(8):1506-17. doi: 10.1128/MCB.06271-11. Epub 2012 Feb 13.
Abstract
PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.
摘要
PALB2/FANCN 在乳腺癌和胰腺癌以及范可尼贫血（FA）中发生突变。它控制 BRCA2 的核内定位、稳定性和 DNA 修复功能，并将 BRCA1 和 BRCA2 联系起来，参与 DNA 同源重组修复和乳腺癌抑制。在这里，我们表明 PALB2 直接与 KEAP1 相互作用，KEAP1 是一种氧化应激传感器，可结合并抑制主抗氧化转录因子 NRF2。PALB2 与 NRF2 具有高度保守的 ETGE 型 KEAP1 结合基序，并且可以有效地与 NRF2 竞争 KEAP1 结合。PALB2 促进 NRF2 在核内积累和发挥功能，并降低细胞内的活性氧（ROS）水平。此外，PALB2 还调节诱导后 NRF2 从核内的输出速度。我们的发现确定 PALB2 为细胞内氧化还原稳态的调节剂，并提供了氧化应激与癌症和 FA 发展之间的新联系。
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本文引用的文献
1
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.BRCA2 相互作用蛋白 PALB2 中的遗传突变对家族性乳腺癌的贡献。
Cancer Res. 2011 Mar 15;71(6):2222-9. doi: 10.1158/0008-5472.CAN-10-3958. Epub 2011 Feb 1.
2
Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.Keap1-Nrf2 通路在应激反应和癌症演化中的分子机制。
Genes Cells. 2011 Feb;16(2):123-40. doi: 10.1111/j.1365-2443.2010.01473.x.
3
A PALB2 mutation associated with high risk of breast cancer.与乳腺癌高风险相关的 PALB2 突变。
Breast Cancer Res. 2010;12(6):R109. doi: 10.1186/bcr2796. Epub 2010 Dec 23.
4
PALB2/FANCN: recombining cancer and Fanconi anemia.PALB2/FANCN：重组癌症与范可尼贫血。
Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21.
5
Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis.通过ChIP-Seq分析和网络分析对Nrf2结合位点进行全基因组图谱绘制，可识别细胞存活反应中的新靶点。
Nucleic Acids Res. 2010 Sep;38(17):5718-34. doi: 10.1093/nar/gkq212. Epub 2010 May 11.
6
PALB2 mutations in European familial pancreatic cancer families.欧洲家族性胰腺癌家系中的 PALB2 突变。
Clin Genet. 2010 Nov;78(5):490-4. doi: 10.1111/j.1399-0004.2010.01425.x.
7
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8
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9
Fanconi anemia proteins and endogenous stresses.范可尼贫血蛋白与内源性应激
Mutat Res. 2009 Jul 31;668(1-2):42-53. doi: 10.1016/j.mrfmmm.2009.03.013.
10
Structural basis for recruitment of BRCA2 by PALB2.PALB2招募BRCA2的结构基础。
EMBO Rep. 2009 Sep;10(9):990-6. doi: 10.1038/embor.2009.126. Epub 2009 Jul 17.
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