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

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-␤-estradiol (10 Ϫ9 -10 Ϫ7 M) could decrease human 1.3-kilobase COMT mRNA levels in MCF-7 cells in a time-and dosedependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5Ј 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-␤-galactosidase plasmids into COS-7 cells, we showed that 17-␤-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.Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme that catalyzes the transfer of the methyl group from the coenzyme S-adenosyl-L-methionine (SAM) to one of the hydroxyl groups of catechols in the presence of Mg 2ϩ (Guldberg and Marsden, 1975). There are two isoforms of COMT of similar function: soluble and membrane-bound (MB). They are encoded by two transcripts [1.3 and 1.5 kilobase (kb) in human] regulated by the proximal and distal promoters, respectively (Tenhunen et al., 1994). The structural differences between these two human transcripts are a 5Ј extension of 150 base pairs (bp), which codes for a signal-anchor domain to direct the MB-COMT polypeptide to membranes, and the presence of a 5Ј noncoding region in the 1.5-kb transcript (Tenhunen et al., 1994).COMT may play an important role in the pathophysiology of different human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension, because the substrates of COMT are catechol estrogens (e.g., carcinogenic 4-hydroxyestradiol), indolic intermediates in melanin metabolism, xenobiotic catechols (e.g., carcinogenic flavonoids), catechol neurotransmitters (e.g., dopamine and noradr...

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

“…This observation is in accordance with previous studies in obsessive-compulsive disorder, panic disorder, and schizophrenia reporting association of the COMT val158met polymorphism preferably in female patients (Alsobrook et al, 2002;Domschke et al, 2004;Kremer et al, 2003). Gender-specific effects of COMT gene variation also fit well with findings of sexually dimorphic COMT activity (Boudikova et al, 1990), which might be due to the fact that estrogen can regulate COMT transcription by binding to estrogen response elements in the promoter region of the COMT gene (Xie et al, 1999). Thus, genderspecific effects of the COMT val158met polymorphism might be due to hormonal influences, gene-gene interaction (eg, with a sex-linked gene), or gene-environment interaction with a gender-specific exposure possibly affecting an intermediate phenotype common to several different psychiatric diseases including major depression.…”

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

“…Surprisingly, we are not aware of such assessments of the COMT variants implicated in psychosis, although such assays have demonstrated the role of EREs in controlling COMT expression, and the distinct role of ERE6 in particular as the only COMT ERE that upregulates COMT expression. 24 Whether a similar degree of LD exists between ERE6 and RS737865 in the populations in which haplotype associations with schizophrenia have been reported is not known, 22,51,55 although LD in this region varies between populations of origin that contribute to our subject pool. 56 Regardless of which locus affects expression, the data suggest that the joint action of alleles at RS4680 and ERE6/RS737865 have a strong impact on risk for AD þ P (Figures 2 and 3), and raise the possibility that variation at ERE6 may impact the risk for schizophrenia or other psychosis in a sexspecific manner.…”

“…23 It was proposed that this mechanism could account for the observation of sexually dimorphic COMT activity. 24 Although the effect of estrogen on COMT, mediated by several of these elements, is to downregulate the expression of COMT, estrogen receptor binding to this specific ERE, ERE6, has been shown to increase expression. 24 Thus, ERE6 could play a role in the sex-differential effects of COMT alleles and haplotypes on liability to schizophrenia recently reported.…”

“…24 Although the effect of estrogen on COMT, mediated by several of these elements, is to downregulate the expression of COMT, estrogen receptor binding to this specific ERE, ERE6, has been shown to increase expression. 24 Thus, ERE6 could play a role in the sex-differential effects of COMT alleles and haplotypes on liability to schizophrenia recently reported. 22 We therefore examined the association between AD þ P and four polymorphisms, RS4680, ERE6, RS737865, and RS165599, as single loci and multilocus haplotypes.…”

The association between headache and Val158Met polymorphism in the catechol–O–methyltransferase gene: the HUNT Study

“…The observation that COMT activity is lower in females than in males and that COMT activity may be under hormonal control [16,17] is the reason for performing separate analyses for each gender. The prevalence of non-migrainous headache tended to be lower among women with the Val/Val genotype than among those with the other genotypes.…”