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Article: Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription

TitleCharacterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription
Authors
Issue Date1999
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 1999, v. 56 n. 1, p. 31-38 How to Cite?
AbstractCatechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-β-estradiol (10-9-10-7 M) could decrease human 1.3- kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-β-galactosidase plasmids into COS-7 cells, we showed that 17-β-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.
Persistent Identifierhttp://hdl.handle.net/10722/162346
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorXie, Ten_US
dc.contributor.authorHo, SLen_US
dc.contributor.authorRamsden, Den_US
dc.date.accessioned2012-09-05T05:19:09Z-
dc.date.available2012-09-05T05:19:09Z-
dc.date.issued1999en_US
dc.identifier.citationMolecular Pharmacology, 1999, v. 56 n. 1, p. 31-38en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/162346-
dc.description.abstractCatechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-β-estradiol (10-9-10-7 M) could decrease human 1.3- kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-β-galactosidase plasmids into COS-7 cells, we showed that 17-β-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshBlotting, Northernen_US
dc.subject.meshCcaat-Enhancer-Binding Proteinsen_US
dc.subject.meshCos Cellsen_US
dc.subject.meshCatechol O-Methyltransferase - Geneticsen_US
dc.subject.meshCloning, Molecularen_US
dc.subject.meshDna-Binding Proteins - Physiologyen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshEstrogens - Pharmacologyen_US
dc.subject.meshGene Expression Regulation - Drug Effectsen_US
dc.subject.meshGenes, Reporteren_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshNuclear Proteins - Physiologyen_US
dc.subject.meshPromoter Regions, Genetic - Genetics - Physiologyen_US
dc.subject.meshSequence Analysis, Dnaen_US
dc.subject.meshTranscription, Genetic - Drug Effectsen_US
dc.titleCharacterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcriptionen_US
dc.typeArticleen_US
dc.identifier.emailHo, SL:slho@hku.hken_US
dc.identifier.authorityHo, SL=rp00240en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid10385681-
dc.identifier.scopuseid_2-s2.0-0033060947en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033060947&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume56en_US
dc.identifier.issue1en_US
dc.identifier.spage31en_US
dc.identifier.epage38en_US
dc.identifier.isiWOS:000081240600004-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridXie, T=7103076362en_US
dc.identifier.scopusauthoridHo, SL=25959633500en_US
dc.identifier.scopusauthoridRamsden, D=7102612805en_US

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