Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes.
BACKGROUND: 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 o...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2887452?pdf=render |
| _version_ | 1811270558571036672 |
|---|---|
| author | Koichi Hasegawa Johji Miwa |
| author_facet | Koichi Hasegawa Johji Miwa |
| author_sort | Koichi Hasegawa |
| collection | DOAJ |
| description | BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 3.5x10(5) 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. CONCLUSIONS/SIGNIFICANCE: 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). |
| first_indexed | 2024-04-12T22:04:01Z |
| format | Article |
| id | doaj.art-796ec2e70c83468fa3dd6f6cf7bfdb81 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T22:04:01Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-796ec2e70c83468fa3dd6f6cf7bfdb812022-12-22T03:15:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0156e1119410.1371/journal.pone.0011194Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes.Koichi HasegawaJohji MiwaBACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 3.5x10(5) 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. CONCLUSIONS/SIGNIFICANCE: 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).http://europepmc.org/articles/PMC2887452?pdf=render |
| spellingShingle | Koichi Hasegawa Johji Miwa Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. PLoS ONE |
| title | Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. |
| title_full | Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. |
| title_fullStr | Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. |
| title_full_unstemmed | Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. |
| title_short | Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. |
| title_sort | genetic and cellular characterization of caenorhabditis elegans mutants abnormal in the regulation of many phase ii enzymes |
| url | http://europepmc.org/articles/PMC2887452?pdf=render |
| work_keys_str_mv | AT koichihasegawa geneticandcellularcharacterizationofcaenorhabditiselegansmutantsabnormalintheregulationofmanyphaseiienzymes AT johjimiwa geneticandcellularcharacterizationofcaenorhabditiselegansmutantsabnormalintheregulationofmanyphaseiienzymes |