Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal.
Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):686-698. doi: 10.1016/j.bbamcr.2019.01.011. Epub 2019 Jan 24.
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 PKCδ, an enzyme controlled by Src tyrosine kinases. Of relevance, Src family members are involved in numerous cellular processes and regulated by hydrogen peroxide (HO). 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 HO. Acute exposure of HT22 mouse hippocampal neural cells to HO 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 PKCδ phosphorylation at Tyr311. We demonstrate, for the first time, c-Src-mediated regulation of Nrf2 transcriptional activity, via PKCδ activation, following an acute HO stimulus. This work supports that the c-Src/PKCδ/Nrf2 pathway may constitute a novel signaling pathway stimulated by HO and a potential target for the treatment of diseases involving redox deregulation.
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发生改变。细胞溶质 Nrf2 的激活通过 PKCδ 的磷酸化调节，PKCδ 是一种受Src 酪氨酸激酶控制的酶。相关的是，Src 家族成员参与许多细胞过程，并受过氧化氢 (HO) 调节。在这项研究中，我们分析了与细胞存活相关的信号蛋白 c-Src 和 Nrf2 的激活，以及 c-Src 激酶对 HO 暴露后 Nrf2 调节的影响。急性暴露于 HO 增加了 HT22 小鼠海马神经细胞中的 c-Src 和 Nrf2 的磷酸化/激活，分别在 Tyr416 和 Ser40 上。Nrf2 在 Ser40 上的磷酸化、其核积累以及涉及血红素加氧酶-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 PKCδ 在 Tyr311 上的磷酸化调节 Nrf2 活性。我们首次证明，在急性 HO 刺激后，通过 PKCδ 激活，c-Src 介导的 Nrf2 转录活性调节。这项工作支持 c-Src/PKCδ/Nrf2 途径可能构成一种新型的 HO 刺激信号通路，并且是涉及氧化还原失调的疾病治疗的潜在靶点。
