Association of thymidylate synthase enhancer region polymorphisms with thymidylate synthase activity in vivo.
Pharmacogenomics J
; 11(4): 307-14, 2011 Aug.
Article
em En
| MEDLINE
| ID: mdl-20531375
ABSTRACT
Two known polymorphisms in the 5' enhancer region (ER) of the thymidylate synthase (TS) gene, a variable number of tandem repeats of a 28 bp sequence (2R/3R) and a further G>C single nucleotide substitution within the repeats, result in genotypes with 0-5 functional upstream stimulatory factor (USF) E-box consensus elements. However, the relationship between these polymorphisms, regulation of TS expression and patient response to fluoropyrimidine treatment has been inconsistent. In this study, seven possible TSER allele configurations showed similar patterns of luciferase gene expression regardless of cell type or USF-1 content, with no significant difference in promoter activity between the wild-type 2RGC and 3RGGC (1.40±0.37 vs 1.43±0.32, P=0.90), whereas the minor alleles, 2RCC and 3RGCC, were significantly reduced (0.84±0.17, P=0.01) and increased (3.19±0.72, P=0.001) respectively. Patient plasma levels of 2'-deoxyuridine, a surrogate marker of TS activity, were significantly different between genotypes (P<0.001) and inversely related to luciferase activity (P=0.02) but not to the absolute number of functional repeated elements (P=0.16), suggesting that the position, rather than the number of functional USF E-box repeats in the TSER, is responsible for determining gene expression in vitro and TS activity in vivo.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Timidilato Sintase
/
Neoplasias Colorretais
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Regulação Enzimológica da Expressão Gênica
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Elementos Facilitadores Genéticos
/
Regiões Promotoras Genéticas
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Sequências de Repetição em Tandem
/
Polimorfismo de Nucleotídeo Único
Tipo de estudo:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
Limite:
Aged
/
Female
/
Humans
/
Male
/
Middle aged
País/Região como assunto:
Oceania
Idioma:
En
Revista:
Pharmacogenomics J
Assunto da revista:
BIOLOGIA MOLECULAR
/
FARMACOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Austrália