Sci. Aging Knowl. Environ., 6 November 2002
Vol. 2002, Issue 44, p. tg12

GENETICALLY ALTERED MICE

Glutamate-Cysteine Ligase Modifier Knockout Mice

http://sageke.sciencemag.org/cgi/content/full/sageke;2002/44/tg12


Mouse Glutamate-cysteine ligase modifier (GCLM) knockout mice
Genetic background 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.
Gene changed 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.
Phenotype 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.
Primary reference 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]
Additional references See below.
Source Not commercially available. Please contact the authors of the primary reference.
Other comments None
Other links OMIM entry for a related human condition: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601176
Keywords glutamate-cysteine ligase (GCL), GCL catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, knockout mouse, glutathione (GSH), cysteine, oxidative stress
Prepared by Qitao Ran


November 6, 2002
  1. 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]
  2. 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]
  3. 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]
  4. 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).
Citation: Glutamate-Cysteine Ligase Modifier Knockout Mice. Science's SAGE KE (6 November 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/44/tg12








Science of Aging Knowledge Environment. ISSN 1539-6150