title: Retinoic acid (RA) receptor transcriptional activation correlates with inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase (ODC) activity by retinoids: a potential role for trans-RA-induced ZBP-89 in ODC inhibition.
abstract: Evaluation of retinoic acid receptor (RAR) subtype-selective alpha and gamma agonists and antagonists and a retinoid X receptor (RXR) class-selective agonist for efficacy at inhibiting both induction of ornithine decarboxylase (ODC) by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis and rat tracheal epithelial cells and the appearance of papillomas in mouse epidermis treated in the 2-stage tumor initiation-promotion model indicated that (i) RXR class-selective transcriptional agonists, such as MM11246, were not involved in ODC inhibition; (ii) RAR-selective agonists that induce gene transcription from RA-responsive elements (RAREs) were active at low concentrations; (iii) RAR-selective antagonists that bind RARs and inhibit AP-1 activation on the collagenase promoter but do not activate RAREs to induce gene transcription were less effective inhibitors; and (iv) RARgamma-selective retinoid agonists were more effective inhibitors of TPA-induced ODC activity than RARalpha-selective agonists. These results suggest that RARE activation has a more important role in inhibition of ODC activity than RXR activation or AP-1 inhibition and that RARgamma-selective agonists would be the most useful inhibitors of epithelial cell proliferation induced by tumor promoters. The natural retinoid all-trans-RA induced expression of transcription factor ZBP-89, which represses activation of the GC box in the ODC promoter by the transcription factor Sp1.
authors.affiliation: Molecular Medicine Research Institute, Mountain View, CA 94043, USA. mdawson@mmrx.org
authors.forename: M I
authors.initials: MI
authors.lastname: Dawson
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Chao
authors.forename: L
authors.initials: L
authors.lastname: Dousman
authors.forename: N
authors.initials: N
authors.lastname: Waleh
authors.forename: P D
authors.initials: PD
authors.lastname: Hobbs
authors.forename: L
authors.initials: L
authors.lastname: Jong
authors.forename: L
authors.initials: L
authors.lastname: Toll
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Gu
authors.forename: A
authors.initials: A
authors.lastname: Agadir
authors.forename: J L
authors.initials: JL
authors.lastname: Merchant
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.forename: A K
authors.initials: AK
authors.lastname: Verma
authors.forename: S M
authors.initials: SM
authors.lastname: Thacher
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: B
authors.initials: B
authors.lastname: Shroot
authors.forename: D L
authors.initials: DL
authors.lastname: Hill
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens; D002470:Cell Survival / Q000187:drug effects; D017364:Collagenases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D009374:Neoplasms, Experimental / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010212:Papilloma / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D014132:Trachea / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014466:Ultraviolet Rays; D000097768:Retinoic Acid Receptor gamma
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D000970:Antineoplastic Agents; D002273:Carcinogens; D017364:Collagenases; D004268:DNA-Binding Proteins; D065108:Ornithine Decarboxylase Inhibitors; D011494:Protein Kinases; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C418636:MM 11254; C418642:MM 11365; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C000607073:Rara protein, rat; C110951:ZNF148 protein, human; C491741:Zfp148 protein, mouse; C491740:Zfp148 protein, rat