Journal article
A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation
The FASEB journal, Vol.25(7), pp.2180-2187
07/2011
Handle:
https://hdl.handle.net/2376/103868
PMCID: PMC3114536
PMID: 21444626
Abstract
A guanine-adenine-guanine (GAG) repeat polymorphism with 5 different alleles (4, 7, 8, 9, and 10 repeats) in the 5′ untranslated region (UTR) of GCLC has been associated with altered GCL activity and glutathione (GSH) levels. We investigated whether this polymorphism affects either transcription or translation using luciferase reporter constructs containing variant GCLC 5′ UTRs. Higher luciferase activity was observed in HepG2 and human embryonic kidney 293 (HEK293) cells transfected with constructs containing either 8 or 9 repeats than in constructs containing 4, 7, or 10 repeats ( P <0.05). In cell-free lysates, GAG repeat number had no effect on luciferase mRNA yield. In vitro translation of mRNAs from luciferase constructs resulted in differences similar to those found in cell cultures ( P <0.05). A similar association of GAG repeat with GCLC phenotype was observed in vivo in healthy adults, as individuals with GAG-7/7 genotype had lower GCL activity and GSH levels in lymphocytes compared to those with GAG-9/9 ( P <0.05). Higher GCL activity and GSH levels observed in red blood cells (RBCs) from individuals with GAG-7/7 compared to GAG-9/9 are likely due to differences in GCL regulation in RBCs. Altogether, these results suggest that GAG polymorphism affects GCLC expression via translation, and thus may be associated with altered risk for GSH-related diseases and toxicities.—Nichenametla, S. N., Lazarus, P., Richie, J. P., Jr. A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation.
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- Title
- A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation
- Creators
- Sailendra N Nichenametla - Molecular Epidemiology and Cancer Control Program, Penn State Cancer InstitutePhilip Lazarus - Molecular Epidemiology and Cancer Control Program, Penn State Cancer InstituteJohn P Richie - Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute
- Publication Details
- The FASEB journal, Vol.25(7), pp.2180-2187
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- Federation of American Societies for Experimental Biology; Bethesda, MD, USA
- Number of pages
- 8
- Grant note
- R01DE013158 / NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR) P01CA068384 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P01-CA68384; R01-DE13158 / U. S. National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Identifiers
- 99900546843101842
- Language
- English
- Resource Type
- Journal article