The significance of Nrf2 pathway in (photo)-oxidative stress response in melanocytes and keratinocytes of the human epidermis
The significance of Nrf2 pathway in (photo)-oxidative stress response in melanocytes and keratinocytes of the human epidermis
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DOI：
10.1111/j.1755-148x.2007.00424.x
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发表时间：
2008-02-01
影响因子：
4.3
通讯作者：
Meunier, Jean-Roch
中科院分区：
文献类型：
--
作者：
Marrot, Laurent;Jones, Christophe;Meunier, Jean-Roch
编码抗氧化剂和/或2相解毒酶的基因的表达可以响应于各种环境胁迫而增强。参与这种反应的主要转录因子是核因子红细胞2相关因子2（Nrf 2）。Nrf 2活性受蛋白Kelch样Ech-associated-protein 1（Keap 1）负调控。虽然Nrf 2和2期基因在化学预防致癌作用中的作用已经得到了很好的描述，但只有很少的研究涉及它们在皮肤癌中的作用。正常人角质形成细胞（NHK）和黑素细胞（NHM）通过Nrf 2途径的化学诱导剂或通过用于敲低Keap 1 mRNA的小干扰RNA（siRNA）处理。上述处理导致NQO-1（NADPH-醌-氧化还原酶1）基因表达的显著刺激。GCL（γ-谷氨酰-半胱氨酰-连接酶）基因也被诱导，但有趣的是，编码催化的重亚基GCLC的mRNA主要在NHK中被刺激，而编码修饰剂轻亚基GCLM的mRNA主要在NHM中被诱导。HO-1（血红素加氧酶1）基因诱导在NHM中相对较强，但在NHK中通常不存在，除了当细胞经受细胞毒性剂量的上述化学品时。暴露于太阳紫外线（UVB + UVA，300-400 nm）或UVA单独（320 -400 nm）证实了这一趋势，但有趣的是，在剂量的细胞生长减少是可比的，UVA通常比太阳紫外线更有效地诱导2期基因。当使用针对Nrf 2的siRNA时，在NHM和NHK中均观察到NQO-1表达的强烈下调，而HO-1表达的降低主要在NHM中检测到。据我们所知，这是第一项比较NHK和NHM中2期基因调控的研究。因此，提出的结果应有助于更好地了解参与皮肤适应环境应力的分子机制。
The expression of genes encoding antioxidant and/or phase 2 detoxifying enzymes can be enhanced in response to various environmental stresses. The main transcription factor involved in this response is nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 activity is negatively regulated by the protein Kelch-like-Ech-associated-protein 1 (Keap1). While the roles of Nrf2 and phase 2 genes in chemoprevention of carcinogenesis have been well described; only few studies have dealt with their role in skin cancer. Normal human keratinocytes (NHK) and melanocytes (NHM) were treated by chemical inducers of the Nrf2 pathway or by small interfering RNAs (siRNA) used to knock down Keap1 mRNA. The above treatments resulted in significant stimulation of NQO-1 (NADPH-Quinone-Oxidoreductase 1) gene expression. GCL (gamma-Glutamyl-cysteinyl-ligase) gene was also induced but interestingly increased mRNA encoding the catalytic, heavy subunit GCLC was mainly stimulated in NHK, whereas the mRNA encoding the modifier, light subunit GCLM was mostly induced in NHM. HO-1 (Heme Oxygenase 1) gene induction was relatively strong in NHM, but generally absent in NHK, except when the cells were subjected to cytotoxic doses of the above chemicals. Exposure to solar UV (UVB + UVA, 300-400 nm) or to UVA alone (320 400 nm) confirmed this trend, but interestingly, at doses where cell growth reduction was comparable, UVA was generally more efficient than solar UV in inducing phase 2 genes. When siRNAs directed against Nrf2 were used, a strong down-regulation of NQO-1 expression was observed in both, NHM and NHK, whereas reduction of HO-1 expression was mainly detected in NHM. To our knowledge, this is the first study comparing phase 2 gene modulation in NHK and NHM. The results hereby presented should contribute to a better understanding of the molecular mechanisms involved in skin adaptation to environmental stress.