TY - JOUR
T1 - Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter
AU - Hsieh, Tsai-Yuan
AU - Shiu, Tzu-Yue
AU - Huang, Shih-Ming
AU - Lin, Hsuan-Hwai
AU - Lee, Tai C.
AU - Chen, Peng-Jen
AU - Chu, Heng-Cheng
AU - Chang, W.-K.
AU - Jeng, King-Song
AU - Lai, Michael M.C.
AU - Chao, Y.-C.
N1 - 被引用次數：35
Export Date: 22 March 2016
通訊地址: Chao, Y.-C.; Department of Internal Medicine, National Defense Medical Center, 325, Cheng-Kung Rd. Sec 2, Neihu 114, Taipei, Taiwan; 電子郵件： [email protected]
化學物質/CAS: bilirubin uridine-diphosphoglucuronosyl transferase 1A1, EC 2.4.1.-; DNA Primers; Glucuronosyltransferase, EC 2.4.1.17; TATA-Box Binding Protein
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PY - 2007
Y1 - 2007
N2 - OBJECTIVES: Gilbert's syndrome is a congenital, nonhemolytic, unconjugated hyperbilirubinemia. The most common genotype of Gilbert's syndrome is the homozygous polymorphism, A(TA)7TAA, in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with a thymine adenine insertion in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. The mechanism responsible for this decrease in UGT1A1 activity, however, has not been elucidated. To clarify the mechanism underlying this deficiency in UGT1A1 activity in patients with Gilbert's syndrome. METHODS: The promoter activity assay using the wild-type A(TA)6TAA or the mutant A(TA)7TAA promoter and a luciferase reporter was performed in two different hepatoma cell lines. The binding affinity for a nuclear protein complex or for TATA-binding protein was evaluated by a competitive electophoretic mobility shift assay using wild-type or mutant TATA-box-like oligonucleotide probes and nuclear extract or TATA-binding protein. The formation of complexes between TATA-binding protein and wild-type or mutant oligonucleotide probes was also studied by a quantitive electophoretic mobility shift assay. RESULTS: A TA insertion in the TATA-box-like sequence of the promoter activity of UGT1A1 gene. A competitive electrophoretic mobility shift assay showed a decrease in nuclear proteincomplex binding affinity and TATA-binding protein binding affinity of the mutant TATA-box-like sequence A(TA)7TAA. When the mutants A(TA)5TAA and A(TA)8TAA were also compared, quantitative electrophoretic mobility shift assay demonstrated that the TATA-binding protein binding affinity progressively decreased as the number of TA repeats in the TATA-box-like sequence increased. CONCLUSION: TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilbert's syndrome. © 2007 Lippincott Williams & Wilkins, Inc.
AB - OBJECTIVES: Gilbert's syndrome is a congenital, nonhemolytic, unconjugated hyperbilirubinemia. The most common genotype of Gilbert's syndrome is the homozygous polymorphism, A(TA)7TAA, in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with a thymine adenine insertion in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. The mechanism responsible for this decrease in UGT1A1 activity, however, has not been elucidated. To clarify the mechanism underlying this deficiency in UGT1A1 activity in patients with Gilbert's syndrome. METHODS: The promoter activity assay using the wild-type A(TA)6TAA or the mutant A(TA)7TAA promoter and a luciferase reporter was performed in two different hepatoma cell lines. The binding affinity for a nuclear protein complex or for TATA-binding protein was evaluated by a competitive electophoretic mobility shift assay using wild-type or mutant TATA-box-like oligonucleotide probes and nuclear extract or TATA-binding protein. The formation of complexes between TATA-binding protein and wild-type or mutant oligonucleotide probes was also studied by a quantitive electophoretic mobility shift assay. RESULTS: A TA insertion in the TATA-box-like sequence of the promoter activity of UGT1A1 gene. A competitive electrophoretic mobility shift assay showed a decrease in nuclear proteincomplex binding affinity and TATA-binding protein binding affinity of the mutant TATA-box-like sequence A(TA)7TAA. When the mutants A(TA)5TAA and A(TA)8TAA were also compared, quantitative electrophoretic mobility shift assay demonstrated that the TATA-binding protein binding affinity progressively decreased as the number of TA repeats in the TATA-box-like sequence increased. CONCLUSION: TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilbert's syndrome. © 2007 Lippincott Williams & Wilkins, Inc.
KW - Electrophoretic mobility shift assay
KW - Gilbert's syndrome
KW - TATA-binding protein
KW - UDP-glucuronosyltransferase 1A1
KW - glucuronosyltransferase 1A1
KW - oligonucleotide
KW - TATA binding protein
KW - amino acid sequence
KW - article
KW - binding affinity
KW - controlled study
KW - enzyme activity
KW - gel mobility shift assay
KW - gene activity
KW - gene insertion
KW - Gilbert disease
KW - hepatoma cell
KW - human
KW - human cell
KW - oligonucleotide probe
KW - pathogenesis
KW - priority journal
KW - promoter region
KW - protein binding
KW - Base Sequence
KW - Cell Line
KW - DNA Primers
KW - Electrophoretic Mobility Shift Assay
KW - Gilbert Disease
KW - Glucuronosyltransferase
KW - Humans
KW - Kinetics
KW - Mutagenesis, Insertional
KW - Pharmacogenetics
KW - Promoter Regions (Genetics)
KW - TATA-Box Binding Protein
U2 - 10.1097/FPC.0b013e328012d0da
DO - 10.1097/FPC.0b013e328012d0da
M3 - Article
SN - 1744-6872
VL - 17
SP - 229
EP - 236
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 4
ER -
