Sci. Aging Knowl. Environ., 6 November 2002
Vol. 2002, Issue 44, p. tg12
GENETICALLY ALTERED MICE
Glutamate-Cysteine Ligase Modifier Knockout Mice
||Glutamate-cysteine ligase modifier (GCLM) knockout mice
||ES cells: 129 SV; blastocysts: C57BL/6. Male chimeric mice were bred against female C57BL/6 mice. The F1 mice with germline transmission of the targeted Gclm locus were allowed to interbreed to generate homozygous Gclm-/- (F2) mice.
||Glutamate-cysteine ligase modifier (Gclm)
|Type of change
||A targeted mutation using a neomycin cassette. A region of exon 1 and the 3' splice donor site of intron 1 of the Gclm gene are mutated.
|Nature of protein
||Glutamate-cysteine ligase (GCL) is the rate-limiting enzyme in the glutathione biosynthesis pathway. GCL is a heterodimer consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM). GCLM is a 30.8-kD protein. It modifies the catalytic activity of GCLC.
||The Gclm-/- mice are viable and fertile. The male Gclm-/- mice show weight loss starting at 5 weeks of age. The GSH level is reduced in tissues of Gclm-/- mice (from 9 to 16%), but the ratio of GSSG/GSH + GSSG is the same in Gclm-/- and wild-type mice. The kinetic property of GCL is changed in Gclm-/- mice. Fetal fibroblasts from Gclm-/- mice are much more sensitive than fetal fibroblasts from wild type mice to hydrogen peroxide exposure.
|Corresponding human phenotype
||A polymorphism in the 5'-flanking region of the human GCLM subunit gene is associated with myocardial infarction [Online Mendelian
Inheritance in Man (OMIM) entry number 601176]. Chronic GSH deficiency has also been suspected as a causative factor in a number of pathologies, including neurodegenerative diseases, aging, diabetes mellitus, cataracts, and AIDS.
||Yi Yang, Matthew Z. Dieter, Ying Chen, Howard G. Shertzer, Daniel W. Nebert, Timothy P. Dalton, Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm-/- knockout mouse: novel model system for a severely compromised oxidative stress response. J. Biol. Chem.15 October 2002 (10.1074/jbc.M209372200). [Abstract]
||Not commercially available. Please contact the authors of the primary reference.
||OMIM entry for a related human condition: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601176
||glutamate-cysteine ligase (GCL), GCL catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, knockout mouse, glutathione (GSH), cysteine, oxidative stress
November 6, 2002
- T. P. Dalton, M. Z. Dieter, R. S. Matlib, N. L. Childs, H. G. Shertzer, M. D. Genter, D. W. Nebert, Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem. Biophys. Res. Commun. 267, 184-189 (2000).[CrossRef][Medline]
- S. Nakamura, K. Kugiyama, S. Sugiyama, S. Miyamoto, S. Koide, H. Fukushima, O. Honda, M. Yoshimura, H. Ogawa, Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Circulation 105, 2968-2973 (2002).[Abstract/Free Full Text]
- Z. Z. Shi, J. Osei-Frimpong, G. Kala, S. V. Kala, R. J. Barrios, G. M. Habib, D. J. Lukin, C. M. Danney, M. M. Matzuk, M. W. Lieberman, Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc. Natl. Acad. Sci. U.S.A. 97, 5101-5106 (2000).[Abstract/Free Full Text]
- Y. Yang, M. Z. Dieter, Y. Chen, H. G. Shertzer, D. W. Nebert, T. P. Dalton, Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm-/- knockout mouse: novel model system for a severely compromised oxidative stress response. J. Biol. Chem. 15 October 2002 (10.1074/jbc.M209372200).
Glutamate-Cysteine Ligase Modifier Knockout Mice. Science's SAGE KE
(6 November 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/44/tg12