Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells.
T-cadherin, a glycosylphosphatidylinositol-modified cadherin subtype, is highly expressed in cardiac and vascular tissues. Neither the functions nor regulation of T-cadherin in these tissues is understood. We have cloned rat T-cadherin cDNA encoding the full length amino acid sequence. The 5(') untranslated nucleotide sequences of rat, mouse, and human T-cadherin contain a conserved GCGTG motif which constitutes the invariant core sequence of dioxin- or xenobiotic-regulatory elements. These elements function as target sites for aryl hydrocarbon receptor/aryl hydrocarbon nuclear translocator (AhR/ARNT) in genes regulated by this transcription factor. Using cultures of rat aortic smooth muscle cells this study presents data revealing T-cadherin as a putative target gene for negative regulation of expression through AHR signalling. Prototypic AHR agonists benzo[a]pyrene (BaP) or 7,12-dimethylbenzanthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) repressed T-cadherin mRNA levels. Repression was antagonized by the cognate AHR antagonist alpha-naphthoflavone (alpha-NF). Repression was insensitive to inhibitors of gene transcription (actinomycin D) or de novo protein synthesis (cycloheximide), suggesting AHR/ARNT functions directly in transcriptional repression of T-cad. Regulation of adhesion proteins through the AHR pathway may represent a novel mechanism of action by atherogenic polycyclic aromatic hydrocarbons.
Niermann
Thomas
T
Department of Research, Cardiovascular Laboratories, ZLF 320, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland.
Schmutz
Sanja
S
Erne
Paul
P
Resink
Thérèse
T
D020121:5' Untranslated Regions; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001571:Benzoflavones / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology
D020121:5' Untranslated Regions; D001571:Benzoflavones; D015820:Cadherins; D004785:Environmental Pollutants; C099972:H-cadherin; D008024:Ligands; D019384:Nucleic Acid Synthesis Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D003609:Dactinomycin; D001564:Benzo(a)pyrene; C011512:alpha-naphthoflavone; D003513:Cycloheximide