Hydroquinone regulates hemeoxygenase-1 expression via modulation of Src kinase activity through thiolation of cysteine residues
Hydroquinone regulates hemeoxygenase-1 expression via modulation of Src kinase activity through thiolation of cysteine residues
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DOI：
10.1016/j.freeradbiomed.2012.12.013
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发表时间：
2013-04-01
影响因子：
7.4
通讯作者：
Cho, Jae Youl
中科院分区：
文献类型：
--
作者：
Byeon, Se Eun;Yu, Tao;Cho, Jae Youl
羟基化苯代谢物对苯二酚（HQ）主要由苯产生，苯是一种重要的工业化学品，也是一种常见的膳食成分。虽然许多论文已经讨论了HQ在致瘤反应中的潜在作用，对苯二酚的免疫抑制和抗炎作用也被考虑在内。在本研究中，我们表征了黄芪及其衍生物诱导血红素加氧酶(HO)-1和其他2相酶的机制。HQ通过增加抗氧化应答元件依赖的Nrf-2的转录激活，上调HO-1的mRNA和蛋白水平。通过siRNA治疗和靶向Src的表达shRNA的逆转录病毒感染，以及暴露于PP2（一种Src激酶抑制剂），可以强烈地消除HO-1的表达，从而诱导Src敲低或缺陷。有趣的是，HQ直接靶向并结合到Src的半胱氨酸-483 （C483）和C400残基的巯基上，可能导致细胞内二硫键的破坏。这些半胱氨酸位点的突变显著增强了Src激酶的活性，这表明这些位点可能在Src激酶活性的调控中起重要作用。因此，我们的数据表明，Src，特别是其C483靶点可以被认为是红旗介导的2期酶诱导的主要分子靶点，这可能与ho -1介导的细胞反应有关，如免疫抑制和抗炎作用。(C) 2012爱思唯尔公司版权所有。
The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous papers have addressed the potential role of HQ in tumorigenic responses, the immunosuppressive and anti-inflammatory effects of hydroquinone have also been considered. In this study, we characterized the mechanism of the induction of hemeoxygenase (HO)-1 and other phase 2 enzymes by HQ and its derivatives. HQ upregulated the mRNA and protein levels of HO-1 by increasing the antioxidant-response element-dependent transcriptional activation of Nrf-2. Src knockdown or deficiency induced via siRNA treatment and infection with a retrovirus expressing shRNA targeting Src, as well as exposure to PP2, a Src kinase inhibitor, strongly abrogated HO-1 expression. Interestingly, HQ directly targeted and bound to the sulfhydryl group of cysteine-483 (C483) and C400 residues of Src, potentially leading to disruption of intracellular disulfide bonds. Src kinase activity was dramatically enhanced by mutation of these cysteine sites, implying that these sites may play an important role in the regulation of Src kinase activity. Therefore, our data suggest that Src and, particularly, its C483 target site can be considered as prime molecular targets of the HQ-mediated induction of phase 2 enzymes, which is potentially linked to HO-1-mediated cellular responses such as immunosuppressive and anti-inflammatory actions. (C) 2012 Elsevier Inc. All rights reserved.