Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes.
Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes.
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DOI：
10.1289/ehp.1002304
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发表时间：
2011-01
影响因子：
10.4
通讯作者：
Pi J
中科院分区：
文献类型：
--
作者：
Zhao R;Hou Y;Xue P;Woods CG;Fu J;Feng B;Guan D;Sun G;Chan JY;Waalkes MP;Andersen ME;Pi J
人类接触无机砷(IAS)是一种强有力的氧化应激源，会导致各种皮肤疾病，包括角化症和皮肤癌。核因子-红系2相关因子1(NRF1，又称NFE2L1)在许多抗氧化反应元件(ARE)依赖基因的表达调控中起着关键作用。我们研究了NRF1在砷诱导的人角质形成细胞抗氧化反应和细胞毒性中的作用。在培养的人角质形成细胞HaCaT细胞中，无机亚砷酸盐(iAs3+)以剂量和时间依赖的方式促进NRF1长亚型(120-140 kDa)的蛋白积累。这些异构体主要聚集在HaCaT细胞的细胞核中。在HaCaT细胞中，慢病毒短发夹状RNA选择性缺失NRF1，导致γ谷氨酸半胱氨酸连接酶催化亚基和调节亚基表达降低，细胞内谷胱甘肽水平降低。作为对iAs3+急性暴露的响应，NRF1-KD细胞中一些ARE依赖基因的诱导明显减弱，包括NAD(P)H：苯醌氧化还原酶1(NQO1)、GCLC和GCLM。然而，沉默NRF1不能改变iAs3诱导的HMOX-1的表达，表明HMOX-1不受NRF1的调节。此外，HaCaT细胞中NRF1的缺失不干扰iAs3+诱导的NRF2聚集，但在基础条件和iAs3+暴露条件下显著降低Kelch样ECH相关蛋白1(Keap1)的水平，提示NRF1和Keap1之间存在潜在的相互作用。与NRF1在一些ARE基因转录调控中的关键作用一致，NRF1的敲除显著增强了iAs3+诱导的细胞毒性和细胞凋亡。在这里，我们首次证明了NRF1的长亚型有助于砷诱导的角质形成细胞的抗氧化反应，并保护细胞免受急性砷细胞毒性。
Human exposure to inorganic arsenic (iAs), a potent oxidative stressor, causes various dermal disorders, including hyperkeratosis and skin cancer. Nuclear factor–erythroid 2–related factor 1 (NRF1, also called NFE2L1) plays a critical role in regulating the expression of many antioxidant response element (ARE)-dependent genes. We investigated the role of NRF1 in arsenic-induced antioxidant response and cytotoxicity in human keratinocytes. In cultured human keratinocyte HaCaT cells, inorganic arsenite (iAs3+) enhanced the protein accumulation of long isoforms (120–140 kDa) of NRF1 in a dose- and time-dependent fashion. These isoforms accumulated mainly in the nuclei of HaCaT cells. Selective deficiency of NRF1 by lentiviral short-hairpin RNAs in HaCaT cells [NRF1-knockdown (KD)] led to decreased expression of γ-glutamate cysteine ligase catalytic subunit (GCLC) and regulatory subunit (GCLM) and a reduced level of intracellular glutathione. In response to acute iAs3+ exposure, induction of some ARE-dependent genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), GCLC, and GCLM, was significantly attenuated in NRF1-KD cells. However, the iAs3-induced expression of heme oxygenase 1 (HMOX-1) was unaltered by silencing NRF1, suggesting that HMOX-1 is not regulated by NRF1. In addition, the lack of NRF1 in HaCaT cells did not disturb iAs3+-induced NRF2 accumulation but noticeably decreased Kelch-like ECH-associated protein 1 (KEAP1) levels under basal and iAs3+-exposed conditions, suggesting a potential interaction between NRF1 and KEAP1. Consistent with the critical role of NRF1 in the transcriptional regulation of some ARE-bearing genes, knockdown of NRF1 significantly increased iAs3+-induced cytotoxicity and apoptosis. Here, we demonstrate for the first time that long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes and protect the cells from acute arsenic cytotoxicity.
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影响因子：
4.8
作者：
Li, JZ;Lee, B;Lee, AS
通讯作者：
Lee, AS
影响因子：
5.3
作者：
Derjuga, A;Gourley, TS;Blank, V
通讯作者：
Blank, V
DOI：
10.1016/s0167-4781(00)00238-4
发表时间：
2000-12-15
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Chan, JY;Kwong, M
通讯作者：
Kwong, M
影响因子：
10.3
作者：
Kojima, Chikara;Ramirez, Dario C.;Waalkes, Michael P.
通讯作者：
Waalkes, Michael P.
影响因子：
16
作者：
Padmanabhan, B;Tong, KI;Yamamoto, M
通讯作者：
Yamamoto, M