c-Src regulates Nrf2 activity through PKCδ after oxidant stimulus
c-Src regulates Nrf2 activity through PKCδ after oxidant stimulus
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DOI：
10.1016/j.bbamcr.2019.01.011
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发表时间：
2019-04-01
影响因子：
5.1
通讯作者：
Cristina Rego, A.
中科院分区：
文献类型：
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作者：
Fao, Ligia;Mota, Sandra I.;Cristina Rego, A.
NRF2是参与细胞防御酶表达的主要转录因子，在几种氧化剂相关疾病中会发生变化。胞内Nrf2的激活是通过PKC Delta的磷酸化来调节的，PKC Delta是一种由Src酪氨酸激酶控制的酶。重要的是，Src家族成员参与许多细胞过程，并受过氧化氢(H_2O_2)的调节。在这项研究中，我们分析了与细胞生存相关的信号蛋白c-Src和Nrf2的激活，以及c-Src激酶在H_2O_2作用下对Nrf2调节的影响。HT22小鼠海马神经细胞暴露于H_2O_2后，c-Src和Nrf2在Tyr416和Ser40的磷酸化/激活分别增加。NRF2在Ser40处的磷酸化、其核聚集和涉及血红素加氧酶-1(HO-1)表达的转录活性依赖于c-Src激酶的激活。此外，c-Src通过Tyr311处的PKC增量磷酸化来调节Nrf2的活性。我们首次证明，在急性H(2)O2刺激下，c-Src通过激活PKCS来调节Nrf2的转录活性。这项工作支持c-Src/PKC Delta/Nrf2通路可能构成了一个受过氧化氢刺激的新的信号通路，并可能成为治疗氧化还原失调性疾病的潜在靶点。
Nrf2 is the main transcription factor involved in expression of cell defense enzymes, which is altered in several oxidant-related disorders. Cytosolic Nrf2 activation is modulated through phosphorylation by PKC delta, an enzyme controlled by Src tyrosine kinases. Of relevance, Src family members are involved in numerous cellular processes and regulated by hydrogen peroxide (H2O2). In this study we analysed the activation of cell survival-related signaling proteins, c-Src and Nrf2, and the influence of c-Src kinase on Nrf2 regulation after exposure to H2O2. Acute exposure of HT22 mouse hippocampal neural cells to H2O2 increased c-Src and Nrf2 phosphorylation/activation at Tyr416 and Ser40, respectively. Nrf2 phosphorylation at Ser40, its nuclear accumulation and transcriptional activity involving heme oxygenase-1 (HO-1) expression were dependent on c-Src kinase activation. Moreover, modulation of Nrf2 activity by c-Src occurred through PKC delta phosphorylation at Tyr311. We demonstrate, for the first time, c-Src-mediated regulation of Nrf2 transcriptional activity, via PKCS activation, following an acute H(2)O2 stimulus. This work supports that the c-Src/PKC delta/Nrf2 pathway may constitute a novel signaling pathway stimulated by H2O2 and a potential target for the treatment of diseases involving redox deregulation.