Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes.
Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes.
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DOI：
10.1371/journal.pone.0011194
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发表时间：
2010-06-17
期刊：
影响因子：
3.7
通讯作者：
Miwa J
中科院分区：
文献类型：
--
作者：
Hasegawa K;Miwa J
第二阶段解毒酶对外来生物和内源性毒物起着重要的保护作用。为了了解外源化合物如何调节II相酶的表达，丙烯酰胺被选为模型外源化合物，因为它能诱导线虫体内大量和各种II相酶，包括大量的谷胱甘肽S转移酶(GST)。为了开始解剖外源基因应答通路(XREP)，通过筛选经甲烷磺酸乙酯(EMS)诱变的约3.5×105株GST：：GFP转基因菌株的基因组，筛选出24株GST表达异常或对丙烯酰胺有调节作用的线虫独立突变体。互补试验将突变体分配给四个不同的基因，分别命名为XREP-1、-2、-3和-4。其中一个基因XREP-1编码WDR-23，WDR-23是WD重复蛋白WDR23的线虫同源物。在没有丙烯酰胺的情况下，XREP-1突变体的功能丧失导致许多GSTs和其他II相酶的组成性表达，而野生型XREP-1等位基因进行DNA构建成功地治愈了该构成酶表达的突变表型。XREP-1突变体的遗传学和细胞学特征表明，丙烯酰胺诱导的大量GST和其他II相酶受到XREP-1(WDR-23)的负调控，XREP-1很可能是哺乳动物Keap1的功能等价物，也可能是线虫线虫的类似物Nrf2(核因子红系相关因子2)的调节因子。
The phase II detoxification enzymes execute a major protective role against xenobiotics as well as endogenous toxicants. To understand how xenobiotics regulate phase II enzyme expression, acrylamide was selected as a model xenobiotic chemical, as it induces a large number and a variety of phase II enzymes, including numerous glutathione S-transferases (GSTs) in Caenorhabditis elegans. To begin dissecting genetically xenobiotics response pathways (xrep), 24 independent mutants of C. elegans that exhibited abnormal GST expression or regulation against acrylamide were isolated by screening about 3.5×105 genomes of gst::gfp transgenic strains mutagenized with ethyl methanesulfonate (EMS). Complementation testing assigned the mutants to four different genes, named xrep-1, -2, -3, and -4. One of the genes, xrep-1, encodes WDR-23, a nematode homologue of WD repeat-containing protein WDR23. Loss-of-function mutations in xrep-1 mutants resulted in constitutive expression of many GSTs and other phase II enzymes in the absence of acrylamide, and the wild-type xrep-1 allele carried on a DNA construct successfully cured the mutant phenotype of the constitutive enzyme expression. Genetic and cellular characterization of xrep-1 mutants suggest that a large number of GSTs and other phase II enzymes induced by acrylamide are under negative regulation by XREP-1 (WDR-23), which is likely to be a functional equivalent of mammalian Keap1 and a regulator of SKN-1, a C. elegans analogue of cap-n-collar Nrf2 (nuclear factor erythroid 2-related factor 2).
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影响因子：
3.8
作者：
Hasegawa, Koichi;Miwa, Satsuki;Miwa, Johji
通讯作者：
Miwa, Johji
影响因子：
4.8
作者：
Johansson, AS;Mannervik, B
通讯作者：
Mannervik, B
影响因子：
12.3
作者：
通讯作者：
--
DOI：
10.1073/pnas.261572998
发表时间：
2001-12-18
影响因子：
11.1
作者：
Gao, XQ;Dinkova-Kostova, AT;Talalay, P
通讯作者：
Talalay, P
影响因子：
3.5
作者：
Hasegawa, Koichi;Miwa, Satsuki;Miwa, Johji
通讯作者：
Miwa, Johji