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

Evaluation of retinoic acid receptor (RAR) subtype-selective alpha and gamm a agonists and antagonists and a retinoid X receptor (RXR) class-selective agonist for efficacy at inhibiting both induction of ornithine decarboxylas e (ODC) by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis and rat tracheal epithelial cells and the appearance of pa pillomas in mouse epidermis treated in the 2-stage tumor initiation-promoti on model indicated that (i) RXR class-selective transcriptional agonists, s uch as MMI1246, were not involved in ODC inhibition; (ii) RAR-selective ago nists that induce gene transcription from RA-responsive elements (RAREs) we re active art low concentrations; (iii) RAR-selective antagonists that bind RARs and inhibit AP-I activation on the collagenase promoter but do not ac tivate RAREs to induce gene transcription were less effective inhibitors; a nd (iv) RAR gamma -selective retinoid agonists were more effective inhibito rs of TPA-induced ODC activity than RAR alpha -selective agonists, These re sults suggest that RARE activation has a more important role in inhibition of ODC activity than RXR activation or AP-I inhibition and that RAR gamma - selective agonists would be the most useful inhibitors of epithelial cell p roliferation induced by tumor promoters. The natural retinoid all-trans-RA induced expression of transcription factor ZBP-89, which represses activati on of the GC box in the ODC promoter by the transcription factor Sp I. (C) 2001 Wiley-Liss, Inc.