Interaction of GAG trinucleotide repeat and C-129T polymorphisms impairs expression of the glutamate-cysteine ligase catalytic subunit gene.

Autor: Butticaz C; Center for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Center of Lausanne, CH-1008 Prilly-Lausanne, Switzerland., Gysin R, Cuénod M, Do KQ
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2011 Mar 01; Vol. 50 (5), pp. 617-23. Date of Electronic Publication: 2010 Dec 13.
DOI: 10.1016/j.freeradbiomed.2010.12.002
Abstrakt: Glutamate cysteine ligase (GCL) catalyzes the rate-limiting step in the de novo synthesis of glutathione (GSH). The catalytic subunit (GCLC) of GCL contains a GAG trinucleotide-repeat (TNR) polymorphism within the 5'-untranslated region (5'-UTR) that has been associated with various human disorders. Although several studies suggest that this variation influences GSH content, its implication for GCLC expression remains unknown. To better characterize its functional significance, we performed reporter gene assays with constructs containing the complete GCLC 5'-UTR upstream of a luciferase gene. Transfection of these vectors into various human cell lines did not reveal any significant differences between 7, 8, 9, or 10 GAG repeats, under either basal or oxidative stress conditions. To correlate these results with the previously described down-regulation induced by the C-129T GCLC promoter polymorphism, combinations of both variations were tested. Interestingly, the -129T allele down-regulates gene expression when combined with 7 GAG but not with 8, 9, or 10 GAG TNRs. This observation was confirmed in primary fibroblast cells, in which the combination of GAG TNR 7/7 and -129C/T genotypes decreased the GCLC protein level. These results provide evidence that interaction of the two variations can efficiently impair GCLC expression and thus suggest its involvement in the pathogenesis of diseases related to GSH metabolism.
(2010 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: