title: Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells.
abstract: Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE) located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β) in cultured smooth muscle cells (SMC) as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA) regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Streb
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Long
authors.forename: Ting-Hein
authors.initials: TH
authors.lastname: Lee
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Chad M
authors.initials: CM
authors.lastname: Kitchen
authors.forename: Mary A
authors.initials: MA
authors.lastname: Georger
authors.forename: Orazio J
authors.initials: OJ
authors.lastname: Slivano
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Carr
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Miano
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D054758:A Kinase Anchor Proteins; C102361:Akap12 protein, rat; D018797:Cell Cycle Proteins; D020033:Protein Isoforms; D012176:Retinoids; D014212:Tretinoin; D017868:Cyclic AMP-Dependent Protein Kinases