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Research ArticleArticle

Characterization and Implications of Estrogenic Down-Regulation of Human Catechol-O-Methyltransferase Gene Transcription

Tao Xie, Shu-Leong Ho and David Ramsden
Molecular Pharmacology July 1999, 56 (1) 31-38; DOI: https://doi.org/10.1124/mol.56.1.31
Tao Xie
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Shu-Leong Ho
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Abstract

Catechol-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.

Footnotes

    • Received December 11, 1998.
    • Accepted March 31, 1999.
  • Send reprint requests to: Dr. S.L. Ho, Division of Neurology, University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. E-mail: slho{at}hkucc.hku.hk

  • ↵1 Database deposition: Human proximal (P1) and distal (P2) promoter regions have been deposited in Genbank/USA with accession numbers and , respectively.

  • This work was supported by grant HKU7283/97M from the Research Grant Council, Hong Kong and grant 335/041/0071 from the Committee on Research and Conference Grants, University of Hong Kong (S.L.H.). X.T. was supported by the Ivy Wu Fellowship and the degree of Ph.D. Studentship Award from the University of Hong Kong. A preliminary account of this study was presented in part at the 5th International Congress of Parkinson’s Disease and Movement Disorders [Mov Disorders (1998) 13:2.117]. This work has been submitted by X.T. as part of his Ph.D. thesis to the University of Hong Kong.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (1)
Molecular Pharmacology
Vol. 56, Issue 1
1 Jul 1999
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Research ArticleArticle

Characterization and Implications of Estrogenic Down-Regulation of Human Catechol-O-Methyltransferase Gene Transcription

Tao Xie, Shu-Leong Ho and David Ramsden
Molecular Pharmacology July 1, 1999, 56 (1) 31-38; DOI: https://doi.org/10.1124/mol.56.1.31

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Research ArticleArticle

Characterization and Implications of Estrogenic Down-Regulation of Human Catechol-O-Methyltransferase Gene Transcription

Tao Xie, Shu-Leong Ho and David Ramsden
Molecular Pharmacology July 1, 1999, 56 (1) 31-38; DOI: https://doi.org/10.1124/mol.56.1.31
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