Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters.

Human genomic DNA fragments containing catechol O-methyltransferase (COMT) sequences were isolated and the exon-intron structure analysed by sequencing, PCR and comparing to the human COMT cDNA sequences. The gene contains six exons, of which exons 1 and 2 are noncoding. MB-ATG and S-ATG codons, responsible for the initiation of translation of the membrane-bound (MB) and soluble (S) forms of the enzyme, are located in exon 3. Two distinct COMT-specific transcripts, 1.3 kb and 1.5 kb, were detected in various human tissues and cell lines. Different quantities of the shorter COMT-specific mRNA in the tissues studied suggest a tissue-specific regulation of the COMT gene at transcriptional level. Mapping of the 5' ends of the COMT mRNAs showed that transcription initiates at multiple sites in two separate DNA regions, which are preceded by functional promoter sequences. The proximal promoter (P1), located between the two translation initiation codons and extending approximately 200 bp upstream of the MB-ATG initiation codon, apparently gives rise to the 1.3-kb S-COMT mRNA (S-mRNA). The distal promoter (P2) is located in a DNA fragment in front of and partly overlapping the transcription-start region of the 1.5-kb transcript, suggesting that it controls the expression of this MB-mRNA. Similarities between the rat and human COMT gene promoters are analyzed.

[1]  I. Ulmanen,et al.  Distribution of catechol-O-methyltransferase enzyme in rat tissues. , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[2]  J. Tenhunen,et al.  Production of rat soluble and membrane-bound catechol O-methyltransferase forms from bifunctional mRNAs. , 1993, The Biochemical journal.

[3]  A. Jalanko,et al.  Structure of the rat catechol-O-methyltransferase gene: separate promoters are used to produce mRNAs for soluble and membrane-bound forms of the enzyme. , 1993, DNA and cell biology.

[4]  S. Pavel.  Dynamics of melanogenesis intermediates. , 1993, The Journal of investigative dermatology.

[5]  B. Emanuel,et al.  Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2. , 1992, Genomics.

[6]  Silke Meyer,et al.  Compilation of vertebrate-encoded transcription factors , 1992, Nucleic Acids Res..

[7]  I. Ulmanen,et al.  Cell‐free synthesis of rat and human catechol O‐methyltransferase , 1991 .

[8]  M. Kozak,et al.  An analysis of vertebrate mRNA sequences: intimations of translational control , 1991, The Journal of cell biology.

[9]  J. Carney,et al.  A Drosophila gene containing the opa repetitive element is exclusively expressed in adult male abdomens. , 1991, Nucleic acids research.

[10]  A. Jalanko,et al.  Cloning and Characterization of Human Placental Catechol--Methyltransferase cDNA , 1991 .

[11]  Z Dembic,et al.  Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  B. Roizman,et al.  The promoter, transcriptional unit, and coding sequence of herpes simplex virus 1 family 35 proteins are contained within and in frame with the UL26 open reading frame , 1991, Journal of virology.

[13]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[14]  C. Passananti,et al.  Protein recognition sites in polyomavirus enhancer: formation of a novel site for NF‐1 factor in an enhancer mutant and characterization of a site in the enhancer D domain. , 1990, The EMBO journal.

[15]  J E Darnell,et al.  Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes , 1989, Molecular and cellular biology.

[16]  M. Kozak.  The scanning model for translation: an update , 1989, The Journal of cell biology.

[17]  S. Kaakkola,et al.  New selective COMT inhibitors: useful adjuncts for Parkinson's disease? , 1989, Trends in pharmacological sciences.

[18]  S. Korsmeyer,et al.  Alternative promoters and exons, somatic mutation and deregulation of the Bcl‐2‐Ig fusion gene in lymphoma. , 1988, The EMBO journal.

[19]  M. Karin,et al.  Transcription factor AP-2 mediates induction by two different signal-transduction pathways: Protein kinase C and cAMP , 1987, Cell.

[20]  B. Dobberstein,et al.  Primary structure of the gene for the murine Ia antigen‐associated invariant chains (Ii). An alternatively spliced exon encodes a cysteine‐rich domain highly homologous to a repetitive sequence of thyroglobulin. , 1987, The EMBO journal.

[21]  X. Breakefield,et al.  Soluble and Particulate Forms of Rat Catechol‐O‐Methyltransferase Distinguished by Gel Electrophoresis and Immune Fixation , 1985, Journal of neurochemistry.

[22]  S. Artavanis-Tsakonas,et al.  opa: A novel family of transcribed repeats shared by the Notch locus and other developmentally regulated loci in D. melanogaster , 1985, Cell.

[23]  M. Wickens,et al.  Role of the conserved AAUAAA sequence: four AAUAAA point mutants prevent messenger RNA 3' end formation. , 1984, Science.

[24]  W. Gerlich,et al.  Large surface proteins of hepatitis B virus containing the pre-s sequence , 1984, Journal of virology.

[25]  D. Jeffery,et al.  Characterization of Membrane‐Bound and Soluble Catechol‐O‐Methyltransferase from Human Frontal Cortex , 1984, Journal of neurochemistry.

[26]  A Francis,et al.  Distinct Cellular Localization of Membrane‐Bound and Soluble Forms of Catechol‐O‐Methyltransferase in Brain , 1983, Journal of neurochemistry.

[27]  A. Rivett,et al.  Contribution of Sulfate Conjugation, Deamination, and O‐Methylation to Metabolism of Dopamine and Norepinephrine in Human Brain , 1982, Journal of neurochemistry.

[28]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[29]  C. Marsden,et al.  Catechol-O-methyl transferase: pharmacological aspects and physiological role. , 1975, Pharmacological reviews.

[30]  H Breuer,et al.  Interactions between estrogens and catechol amines. 3. Studies on the methylation of catechol estrogens, catechol amines and other catechols by the ctechol-O-methyltransferases of human liver. , 1972, The Journal of clinical endocrinology and metabolism.

[31]  J. Axelrod,et al.  Enzymatic O-methylation of epinephrine and other catechols. , 1958, The Journal of biological chemistry.

[32]  R. Winqvist,et al.  The human catechol-O-methyltransferase (COMT) gene maps to band q11.2 of chromosome 22 and shows a frequent RFLP with BglI. , 1992, Cytogenetics and cell genetics.

[33]  N. Kalkkinen,et al.  Molecular cloning and characterization of rat liver catechol-O-methyltransferase. , 1990, Gene.

[34]  Wyatt Rj,et al.  Neurotransmitter-related enzymes in the major psychiatric disorders: I. Catechol-O-methyl transferase, monoamine oxidase in the affective disorders, and factors affecting some behaviorally correlated enzyme activities. , 1975 .