Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter

Tsai-Yuan Hsieh, Tzu-Yue Shiu, Shih-Ming Huang, Hsuan-Hwai Lin, Tai C. Lee, Peng-Jen Chen, Heng-Cheng Chu, W.-K. Chang, King-Song Jeng, Michael M.C. Lai, Y.-C. Chao

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)229-236
Number of pages8
JournalPharmacogenetics and Genomics
Volume17
Issue number4
DOIs
Publication statusPublished - 2007
Externally publishedYes

Fingerprint

Gilbert Disease
TATA-Box Binding Protein
TATA Box
Protein Binding
Electrophoretic Mobility Shift Assay
Genes
Oligonucleotide Probes
Hyperbilirubinemia
Thymine
Adenine
Nuclear Proteins
Luciferases
UGT1A1 enzyme
Hepatocellular Carcinoma
Genotype
Cell Line

Keywords

  • Electrophoretic mobility shift assay
  • Gilbert's syndrome
  • TATA-binding protein
  • UDP-glucuronosyltransferase 1A1
  • glucuronosyltransferase 1A1
  • oligonucleotide
  • TATA binding protein
  • amino acid sequence
  • article
  • binding affinity
  • controlled study
  • enzyme activity
  • gel mobility shift assay
  • gene activity
  • gene insertion
  • Gilbert disease
  • hepatoma cell
  • human
  • human cell
  • oligonucleotide probe
  • pathogenesis
  • priority journal
  • promoter region
  • protein binding
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Electrophoretic Mobility Shift Assay
  • Gilbert Disease
  • Glucuronosyltransferase
  • Humans
  • Kinetics
  • Mutagenesis, Insertional
  • Pharmacogenetics
  • Promoter Regions (Genetics)
  • TATA-Box Binding Protein

Cite this

Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. / Hsieh, Tsai-Yuan; Shiu, Tzu-Yue; Huang, Shih-Ming; Lin, Hsuan-Hwai; Lee, Tai C.; Chen, Peng-Jen; Chu, Heng-Cheng; Chang, W.-K.; Jeng, King-Song; Lai, Michael M.C.; Chao, Y.-C.

In: Pharmacogenetics and Genomics, Vol. 17, No. 4, 2007, p. 229-236.

Research output: Contribution to journalArticle

Hsieh, T-Y, Shiu, T-Y, Huang, S-M, Lin, H-H, Lee, TC, Chen, P-J, Chu, H-C, Chang, W-K, Jeng, K-S, Lai, MMC & Chao, Y-C 2007, 'Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter', Pharmacogenetics and Genomics, vol. 17, no. 4, pp. 229-236. https://doi.org/10.1097/FPC.0b013e328012d0da
Hsieh, Tsai-Yuan ; Shiu, Tzu-Yue ; Huang, Shih-Ming ; Lin, Hsuan-Hwai ; Lee, Tai C. ; Chen, Peng-Jen ; Chu, Heng-Cheng ; Chang, W.-K. ; Jeng, King-Song ; Lai, Michael M.C. ; Chao, Y.-C. / Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. In: Pharmacogenetics and Genomics. 2007 ; Vol. 17, No. 4. pp. 229-236.
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title = "Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter",
abstract = "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. {\circledC} 2007 Lippincott Williams & Wilkins, Inc.",
keywords = "Electrophoretic mobility shift assay, Gilbert's syndrome, TATA-binding protein, UDP-glucuronosyltransferase 1A1, glucuronosyltransferase 1A1, oligonucleotide, TATA binding protein, amino acid sequence, article, binding affinity, controlled study, enzyme activity, gel mobility shift assay, gene activity, gene insertion, Gilbert disease, hepatoma cell, human, human cell, oligonucleotide probe, pathogenesis, priority journal, promoter region, protein binding, Base Sequence, Cell Line, DNA Primers, Electrophoretic Mobility Shift Assay, Gilbert Disease, Glucuronosyltransferase, Humans, Kinetics, Mutagenesis, Insertional, Pharmacogenetics, Promoter Regions (Genetics), TATA-Box Binding Protein",
author = "Tsai-Yuan Hsieh and Tzu-Yue Shiu and Shih-Ming Huang and Hsuan-Hwai Lin and Lee, {Tai C.} and Peng-Jen Chen and Heng-Cheng Chu and W.-K. Chang and King-Song Jeng and Lai, {Michael M.C.} and Y.-C. Chao",
note = "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: gi@mail.ndmctsgh.edu.tw 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 參考文獻: Sieg, A., Arab, L., Schlierf, G., Stiehl, A., Kommerell, B., Prevalence of Gilbert's syndrome in Germany (1997) Dtsch Med Wochenschr, 112, pp. 1206-1208; Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., de Boer, A., Oostra, B.A., The genetic basis of the reduced expression of bilirubin UDPglucuronosyltransferase 1 in Gilbert's syndrome (1995) N Engl J Med, 333, pp. 1171-1175; Monaghan, G., Ryan, M., Seddon, R., Hume, R., Burchell, B., Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome (1996) Lancet, 347, pp. 578-581; Beutler, E., Gelbart, T., Demina, A., Racial variability in the UDPglucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? (1998) Proc Natl Acad Sci U S A, 95, pp. 8170-8174; Biondi, M.L., Turri, O., Dilillo, D., Stival, G., Guagnellini, E., Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin concentrations in the Italian population (1999) Clin Chem, 45, pp. 897-898; Lampe, J.W., Bigler, J., Horner, N.K., Potter, J.D., UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: Relationships to serum bilirubin concentrations (1999) Pharmacogenetics, 9, pp. 341-349; Borlak, J., Thum, T., Landt, O., Erb, K., Hermann, R., Molecular diagnosis of a familial non-hemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects (2000) Hepatology, 32, pp. 792-795; Raijmakers, M.T., Jansen, P.L., Steegers, E.A., Peters, W.H., Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene (2000) J Hepatol, 33, pp. 348-351; Black, M., Billing, B.H., Hepatic bilirubin UDP-glucuronyltransferase activity in liver disease and Gilbert's syndrome (1969) N Engl J Med, 280, pp. 1266-1271; De Morais, S.M., Uetrecht, J.P., Wells, P.G., Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome (1992) Gastroenterology, 102, pp. 577-586; Aono, S., Adachi, Y., Uyama, E., Yamada, Y., Keino, H., Nanno, T., Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome (1995) Lancet, 345, pp. 958-959; van Es, H.H., Bout, A., Liu, J., Anderson, L., Duncan, A.M., Bosma, P., Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37 (1993) Cytogenet Cell Genet, 63, pp. 114-116; Ritter, J.K., Chen, F., Sheen, Y.Y., Tran, H.M., Kimura, S., Yeatman, M.T., A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDPglucuronosyltransferase isozymes with identical carboxyl termini (1992) J Biol Chem, 267, pp. 3257-3261; Mackenzie, P.I., Walter Bock, K., Burchell, B., Guillemette, C., Ikushiro, S., Iyanagi, T., Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily (2005) Pharmacogenet Genomic, 15, pp. 677-685; Owens, I.S., Basu, N.K., Banerjee, R., UDP-glucuronosyltransferases: Gene structures of UGT1 and UGT2 families (2005) Methods Enzymol, 400, pp. 1-22; Bosma, P.J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink, R.P., Chowdhury, J.R., Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man (1994) J Biol Chem, 269, pp. 17960-17964; Ideo, G., De Franchis, R., Del Ninno, E., Dioguardi, N., Ethanol increases liver uridine-diphosphate-glucuronyltransferase (1971) Experientia, 27, pp. 24-25; Ritter, J.K., Kessler, F.K., Thompson, M.T., Grove, A.D., Auyeung, D.J., Fisher, R.A., Expression and inducibility of the human bilirubin UDPglucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences (1999) Hepatology, 30, pp. 476-484; Kanou, M., Usui, T., Ueyama, H., Sato, H., Ohkubo, I., Mizutani, T., Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone (2004) Mol Biol Rep, 31, pp. 151-158; Ramirez, J., Komoroski, B.J., Mirkov, S., Graber, A.Y., Fackenthal, D.L., Schuetz, E.G., Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes (2006) Pharmacogenet Genomic, 16, pp. 79-86; Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.H., The phenobarbital response enhancer module in the human bilirubin UDPglucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR (2001) Hepatology, 33, pp. 1232-1238; Xie, W., Yueh, M.F., Radominska-Pandya, A., Saini, S.P., Negishi, Y., Bottroff, B.S., Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor (2003) Proc Natl Acad Sci U S A, 100, pp. 4150-4155; Yueh, M.F., Huang, Y.H., Hiller, A., Chen, S., Nguyen, N., Tukey, R.H., Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1 (2003) J Biol Chem, 278, pp. 15001-15006; Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus (2005) J Biol Chem, 280, pp. 37547-37557; Sugatani, J., Sueyoshi, T., Negishi, M., Miwa, M., Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnaneXreceptor, and glucocorticoid receptor (2005) Methods Enzymol, 400, pp. 92-104; Wagner, M., Halilbasic, E., Marschall, H.U., Zollner, G., Fickert, P., Langner, C., CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice (2005) Hepatology, 42, pp. 420-430; Assenat, E., Gerbal-Chaloin, S., Larrey, D., Saric, J., Fabre, J.M., Maurel, P., Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance (2004) Hepatology, 40, pp. 951-960; Richardson, T.A., Sherman, M., Kalman, D., Morgan, E.T., Expression of UDP-glucuronosyltransferase isoform mRNAs during inflammation and infection in mouse liver and kidney (2006) Drug Metab Dispos, 34, pp. 351-353; Takeuchi, K., Kobayashi, Y., Tamaki, S., Ishihara, T., Maruo, Y., Araki, J., Genetic polymorphisms of bilirubin uridine diphosphate- glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects (2004) J Gastroenterol Hepatol, 19, pp. 1023-1028; Hernandez N. TBP, a universal eukaryotic transcription factor? Genes Dev 1993; 7:1291-1308Patikoglou, G., Burley, S.K., Eukaryotic transcription factor-DNA complexes (1997) Annu Rev Biophys Biomol Struct, 26, pp. 289-325; Wobbe, C.R., Struhl, K., Yeast and human TATA-binding proteins have nearly identical DNA sequence requirements for transcription in vitro (1990) Mol Cell Biol, 10, pp. 3859-3867; Rechkoblit, O., Krzeminsky, J., Amin, S., Jernstrom, B., Louneva, N., Geacintov, N.E., Influence of bulky polynuclear carcinogen lesions in a TATA promoter sequence on TATA binding protein-DNA complex formation (2001) Biochemistry, 40, pp. 5622-5632; Farheen, S., Sengupta, S., Santra, A., Pal, S., Dhali, G.K., Chakravorty, M., Gilbert's syndrome: High frequency of the (TA) (7) TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene (2006) World J Gastroenterol, 12, pp. 2269-2275; Rowlands, T., Baumann, P., Jackson, S.P., The TATA-binding protein: A general transcription factor in eukaryotes and archaebacteria (1994) Science, 264, pp. 1326-1329; Greenblatt, J., Roles of TFIID in transcriptional initiation by RNA polymerase II (1991) Cell, 66, pp. 1067-1070; Killeen, M., Coulombe, B., Greenblatt, J., Recombinant TBP, transcription factor IIB, and RAP30 are sufficient for promoter recognition by mammalian RNA polymerase II (1992) J Biol Chem, 267, pp. 9463-9466; Starr, D.B., Hawley, D.K., TFIID binds in the minor groove of the TATA box (1991) Cell, 67, pp. 1231-1240; Zhang, Q., Broyde, S., Schlick, T., Deformations of promoter DNA bound to carcinogens help interpret effects on TATA-element structure and activity (2004) Philos Transact A Math Phys Eng Sci, 362, pp. 1479-1496; Strahs, D., Barash, D., Qian, X., Schlick, T., Sequence-dependent solution structure and motions of 13 TATA/TBP (TATA-box binding protein) complexes (2003) Biopolymers, 69, pp. 216-243; Bucher, P., Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences (1990) J Mol Biol, 212, pp. 563-578; Seeman, N.G., Rosenberg, J.M., Rich, A., Sequence-specific recognition of double helical nucleic acids by proteins (1976) Proc Natl Acad Sci U S A, 73, pp. 804-808; Faiger, H., Ivanchenko, M., Cohen, I., Haran, T.E., TBP flanking sequences: Asymmetry of binding, long-range effects and consensus sequences (2006) Nucleic Acids Res, 34, pp. 104-119; Librizzi, M.D., Brenowitz, M., Willis, I.M., The TATA element and its context affect the cooperative interaction of TATA-binding protein with the TFIIB-related factor, TFIIIB70 (1998) J Biol Chem, 273, pp. 4563-4568; Wolner, B.S., Gralla, J.D., Roles for non-TATA core promoter sequences in transcription and factor binding (2000) Mol Cell Biol, 20, pp. 3608-3615",
year = "2007",
doi = "10.1097/FPC.0b013e328012d0da",
language = "English",
volume = "17",
pages = "229--236",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

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: gi@mail.ndmctsgh.edu.tw 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 參考文獻: Sieg, A., Arab, L., Schlierf, G., Stiehl, A., Kommerell, B., Prevalence of Gilbert's syndrome in Germany (1997) Dtsch Med Wochenschr, 112, pp. 1206-1208; Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., de Boer, A., Oostra, B.A., The genetic basis of the reduced expression of bilirubin UDPglucuronosyltransferase 1 in Gilbert's syndrome (1995) N Engl J Med, 333, pp. 1171-1175; Monaghan, G., Ryan, M., Seddon, R., Hume, R., Burchell, B., Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome (1996) Lancet, 347, pp. 578-581; Beutler, E., Gelbart, T., Demina, A., Racial variability in the UDPglucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? (1998) Proc Natl Acad Sci U S A, 95, pp. 8170-8174; Biondi, M.L., Turri, O., Dilillo, D., Stival, G., Guagnellini, E., Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin concentrations in the Italian population (1999) Clin Chem, 45, pp. 897-898; Lampe, J.W., Bigler, J., Horner, N.K., Potter, J.D., UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: Relationships to serum bilirubin concentrations (1999) Pharmacogenetics, 9, pp. 341-349; Borlak, J., Thum, T., Landt, O., Erb, K., Hermann, R., Molecular diagnosis of a familial non-hemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects (2000) Hepatology, 32, pp. 792-795; Raijmakers, M.T., Jansen, P.L., Steegers, E.A., Peters, W.H., Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene (2000) J Hepatol, 33, pp. 348-351; Black, M., Billing, B.H., Hepatic bilirubin UDP-glucuronyltransferase activity in liver disease and Gilbert's syndrome (1969) N Engl J Med, 280, pp. 1266-1271; De Morais, S.M., Uetrecht, J.P., Wells, P.G., Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome (1992) Gastroenterology, 102, pp. 577-586; Aono, S., Adachi, Y., Uyama, E., Yamada, Y., Keino, H., Nanno, T., Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome (1995) Lancet, 345, pp. 958-959; van Es, H.H., Bout, A., Liu, J., Anderson, L., Duncan, A.M., Bosma, P., Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37 (1993) Cytogenet Cell Genet, 63, pp. 114-116; Ritter, J.K., Chen, F., Sheen, Y.Y., Tran, H.M., Kimura, S., Yeatman, M.T., A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDPglucuronosyltransferase isozymes with identical carboxyl termini (1992) J Biol Chem, 267, pp. 3257-3261; Mackenzie, P.I., Walter Bock, K., Burchell, B., Guillemette, C., Ikushiro, S., Iyanagi, T., Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily (2005) Pharmacogenet Genomic, 15, pp. 677-685; Owens, I.S., Basu, N.K., Banerjee, R., UDP-glucuronosyltransferases: Gene structures of UGT1 and UGT2 families (2005) Methods Enzymol, 400, pp. 1-22; Bosma, P.J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink, R.P., Chowdhury, J.R., Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man (1994) J Biol Chem, 269, pp. 17960-17964; Ideo, G., De Franchis, R., Del Ninno, E., Dioguardi, N., Ethanol increases liver uridine-diphosphate-glucuronyltransferase (1971) Experientia, 27, pp. 24-25; Ritter, J.K., Kessler, F.K., Thompson, M.T., Grove, A.D., Auyeung, D.J., Fisher, R.A., Expression and inducibility of the human bilirubin UDPglucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences (1999) Hepatology, 30, pp. 476-484; Kanou, M., Usui, T., Ueyama, H., Sato, H., Ohkubo, I., Mizutani, T., Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone (2004) Mol Biol Rep, 31, pp. 151-158; Ramirez, J., Komoroski, B.J., Mirkov, S., Graber, A.Y., Fackenthal, D.L., Schuetz, E.G., Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes (2006) Pharmacogenet Genomic, 16, pp. 79-86; Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.H., The phenobarbital response enhancer module in the human bilirubin UDPglucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR (2001) Hepatology, 33, pp. 1232-1238; Xie, W., Yueh, M.F., Radominska-Pandya, A., Saini, S.P., Negishi, Y., Bottroff, B.S., Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor (2003) Proc Natl Acad Sci U S A, 100, pp. 4150-4155; Yueh, M.F., Huang, Y.H., Hiller, A., Chen, S., Nguyen, N., Tukey, R.H., Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1 (2003) J Biol Chem, 278, pp. 15001-15006; Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus (2005) J Biol Chem, 280, pp. 37547-37557; Sugatani, J., Sueyoshi, T., Negishi, M., Miwa, M., Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnaneXreceptor, and glucocorticoid receptor (2005) Methods Enzymol, 400, pp. 92-104; Wagner, M., Halilbasic, E., Marschall, H.U., Zollner, G., Fickert, P., Langner, C., CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice (2005) Hepatology, 42, pp. 420-430; Assenat, E., Gerbal-Chaloin, S., Larrey, D., Saric, J., Fabre, J.M., Maurel, P., Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance (2004) Hepatology, 40, pp. 951-960; Richardson, T.A., Sherman, M., Kalman, D., Morgan, E.T., Expression of UDP-glucuronosyltransferase isoform mRNAs during inflammation and infection in mouse liver and kidney (2006) Drug Metab Dispos, 34, pp. 351-353; Takeuchi, K., Kobayashi, Y., Tamaki, S., Ishihara, T., Maruo, Y., Araki, J., Genetic polymorphisms of bilirubin uridine diphosphate- glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects (2004) J Gastroenterol Hepatol, 19, pp. 1023-1028; Hernandez N. TBP, a universal eukaryotic transcription factor? 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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

VL - 17

SP - 229

EP - 236

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 4

ER -