Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway - Identification of novel gene clusters for cell survival
Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway - Identification of novel gene clusters for cell survival
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DOI：
10.1074/jbc.m211898200
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发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Kensler, TW
中科院分区：
文献类型：
--
作者：
Kwak, MK;Wakabayashi, N;Kensler, TW
酶诱导剂如3 H-1，2-二硫杂环戊烯-3-基（D3 T）可增强环境致癌物的解毒作用并防止肿瘤形成。诱导物的假定分子传感器是Keap 1，一种富含巯基的蛋白质，其在细胞质中隔离转录因子Nrf 2。这些解毒酶的表达在nrf 2缺陷小鼠中是钝的;此外，这些小鼠对致癌作用更敏感，并且随着nrf 2的破坏，二硫代硫酮的保护作用丧失。通过寡核苷酸微阵列分析，在溶剂或D3 T处理的野生型小鼠以及nrf 2单敲除和keap 1-nrf 2双敲除小鼠中检查肝脏基因表达谱，以鉴定由Keap 1-Nrf 2途径调节的那些基因。在野生型小鼠中，292个基因的转录水平在用D3 T治疗后24小时升高;这些基因中的79%在野生型小鼠中诱导，但在nrf 2缺陷型小鼠中不诱导。这些nrf 2依赖的D3 T诱导基因包括已知的解毒和抗氧化酶。意想不到的簇包括分子伴侣、蛋白质运输、泛素/26 S蛋白酶体亚基和信号分子的基因。keap 1-nrf 2双基因敲除小鼠的基因表达模式与nrf 2单基因敲除小鼠相似。D3 T还导致在24 h时31个基因的nrf 2依赖性抑制;主要是与胆固醇/脂质生物合成相关的基因。总的来说，D3 T通过Keap 1-Nrf 2信号通路增加基因的表达，直接解毒毒素并产生必需的辅因子，如谷胱甘肽和还原当量。参与识别和修复/清除受损蛋白的nrf 2依赖性基因的诱导将该途径的作用从亲电和氧化应激的初级控制扩展到增强细胞存活的次级保护作用。
Enzyme inducers such as 3H-1,2-dithiole-3-thione (D3T) enhance the detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for inducers is Keap1, a sulfhydryl-rich protein that sequesters the transcription factor Nrf2 in the cytoplasm. Expression of these detoxication enzymes is blunted in nrf2-deficient mice; moreover, these mice are more sensitive to carcinogenesis, and the protective actions of dithiolethiones are lost with nrf2 disruption. Hepatic gene expression profiles were examined by oligonucleotide microarray analysis in vehicle-or D3T-treated wild-type mice as well as in nrf2 single and keap1-nrf2 double knockout mice to identify those genes regulated by the Keap1-Nrf2 pathway. Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but not nrf2-deficient mice. These nrf2-dependent, D3T-inducible genes included known detoxication and antioxidative enzymes. Unexpected clusters included genes for chaperones, protein trafficking, ubiquitin/26 S proteasome subunits, and signaling molecules. Gene expression patterns in keap1-nrf2 double knockout mice were similar to those in nrf2-single knockout mice. D3T also led to nrf2-dependent repression of 31 genes at 24 h; principally genes related to cholesterol/lipid biosynthesis. Collectively, D3T increases the expression of genes through the Keap1-Nrf2 signaling pathway that directly detoxify toxins and generate essential cofactors such as glutathione and reducing equivalents. Induction of nrf2-dependent genes involved in the recognition and repair/removal of damaged proteins expands the role of this pathway beyond primary control of electrophilic and oxidative stresses into secondary protective actions that enhance cell survival.