Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses.
Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses.
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DOI：
10.1038/onc.2017.221
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发表时间：
2017-11-02
期刊：
影响因子：
8
通讯作者：
de la Vega L
中科院分区：
文献类型：
--
作者：
Torrente L;Sanchez C;Moreno R;Chowdhry S;Cabello P;Isono K;Koseki H;Honda T;Hayes JD;Dinkova-Kostova AT;de la Vega L
同源结构域相互作用蛋白激酶-2（HIPK 2）是调节细胞生长、凋亡、增殖和发育的应激应答激酶的HIPK家族的成员。HIPK 2具有几种良好的肿瘤抑制作用，但最近的研究表明，它也可能有助于肿瘤进展，尽管其潜在机制尚不清楚。在此，我们已经确定了HIPK 2和细胞保护性转录因子NRF 2之间的新串扰。我们表明，HIPK 2是一个直接的转录靶点的NRF 2，确定一个功能性NRF 2结合位点的HIPK 2基因位点，并首次证明了这种激酶的转录调控模式。此外，HIPK 2是细胞和体内稳健的NRF 2应答所必需的。通过使用功能获得和功能丧失的方法，我们证明了HIPK 2可以通过NRF 2在癌细胞中引起细胞保护反应。我们的研究结果揭示了HIPK 2的一种新的下游效应子NRF 2，它在与化疗耐药性和预后不良相关的人类肿瘤中经常被激活。此外，我们的结果表明，HIPK 2水平或活性的调节可以用来损害癌细胞中NRF 2介导的信号传导，从而使它们对化疗药物敏感。
Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.
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影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
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作者：
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通讯作者：
Schmitz, M. Lienhard
影响因子：
4.6
作者：
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通讯作者：
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