Regulation of genes encoding NAD(P)H:quinone oxidoreductases
Regulation of genes encoding NAD(P)H:quinone oxidoreductases
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DOI：
10.1016/s0891-5849(00)00306-3
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发表时间：
2000-08-01
影响因子：
7.4
通讯作者：
Jaiswal, AK
中科院分区：
文献类型：
--
作者：
Jaiswal, AK
NAD（P）H：醌氧化还原酶（NQO1）和NRH：醌氧化还原酶（NQO2）是催化醌及其衍生物的双电子还原和解毒的黄素蛋白。这导致保护细胞免受氧化还原循环、氧化应激和肿瘤形成。NQO1在所有组织中普遍表达。然而，表达水平在人体组织中存在差异。与类似来源的正常组织相比，NQO1基因在几种肿瘤组织类型（包括肝脏和结肠）中的表达水平更高。NQO1基因表达与其他解毒酶基因协同诱导，以响应外源性物质、抗氧化剂、氧化剂、重金属和辐射。在NQO1基因启动子中的缺失突变鉴定了几个顺式元件，包括抗氧化反应元件（ARE）、基础元件和AP-2元件。ARE元件也被发现存在于其他解毒酶基因的启动子区域，包括谷胱甘肽S-转移酶。ARE是NQO1和其他解毒酶基因表达和协调诱导所必需的。核转录因子Nrf2和c-Jun与ARE结合并激活基因表达。Nrf2 + c-Jun与ARE的结合需要未知的胞质因子。除Nrf2和c-Jun外，其他核转录因子包括Nrf1、Jun-B和Jun-D也与ARE结合，并调节NQO1基因的表达和诱导。基于ARE介导的解毒酶基因调控的现有信息，提出了一个假设模型。简单地说，在未处理的正常细胞中，Nrf2通过阻遏蛋白Keap 1保留在细胞膜中。用外源性物质和抗氧化剂处理细胞导致催化Nrf2和/或Keap 1修饰的未知胞质因子的活化。该修饰遵循Nrf2和Keap1的解离。游离的Nrf2在细胞核中易位。核中的Nrf2与c-Jun异二聚化并结合ARE，导致诱导NQO1和其他ARE调节的基因表达。胞质因子的身份仍然未知。(C)2000 Elsevier Science Inc.
NAD(P)H:quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase (NQO2) are flavoproteins that catalyze two-electron reduction and detoxification of quinones and its derivatives. This leads to the protection of cells against redox cycling, oxidative stress, and neoplasia. NQO1 is expressed ubiquitously in all the tissues. However, the level of expression varied among the human tissues. NQO1 gene is expressed at higher levels in several tumor tissue types, including liver and colon, as compared to normal tissues of similar origin. NQO1 gene expression is coordinately induced with other detoxifying enzyme genes in response to xenobiotics, antioxidants, oxidants, heavy metals, and radiations. Deletion mutagenesis in the NQO1 gene promoter identified several cis-elements including antioxidant response element (ARE), a basal element, and AP-2 element. ARE elements have also been found in the promoter regions of other detoxifying enzyme genes including glutathione S-transferases. ARE is essentially required for expression and coordinated induction of NQO1 and other detoxifying enzyme genes. Nuclear transcription factors Nrf2 and c-Jun bind to the ARE and activate the gene expression. The binding of Nrf2 + c-Jun to the ARE required unknown cytosolic factor(s). In addition to Nrf2 and c-Jun, other nuclear transcription factors including Nrf1, Jun-B, and Jun-D also bind to the ARE: and regulate expression and induction of NQO1 gene. A hypothetical model is presented based on the available information on ARE-mediated regulation of detoxifying enzyme genes. Briefly, the Nrf2 is retained in the cytosplasm by a repressor protein Keap1 in untreated normal cells. The treatment of cells with xenobiotics and antioxidants leads to the activation of unknown cytosolic factor(s) that catalyze modification of Nrf2 and/or Keap1. The modification follows dissociation of Nrf2 and Keap1. The free Nrf2 translocates in the nucleus. Nrf2 in the nucleus heterodimerizes with c-Jun and binds to the ARE resulting in the induction of NQO1 and other ARE-regulated genes expression. The identity of cytosolic factor(s) remains unknown. (C) 2000 Elsevier Science Inc.