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

Int J Cancer. 2001 Jan 1;91(1):8-21. doi: 10.1002/1097-0215(20010101)91:1<8::aid-ijc1007>3.0.co;2-h.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Carcinogens
  • Cell Survival / drug effects
  • Collagenases / genetics
  • DNA-Binding Proteins / physiology*
  • Dose-Response Relationship, Drug
  • Epidermis / metabolism
  • Epithelial Cells / metabolism
  • Female
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Hairless
  • Neoplasms, Experimental / metabolism
  • Ornithine Decarboxylase Inhibitors*
  • Papilloma / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Kinases / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / metabolism*
  • Response Elements
  • Retinoic Acid Receptor alpha
  • Retinoids / metabolism*
  • Retinoids / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Time Factors
  • Trachea / metabolism
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Ultraviolet Rays

Substances

  • Antineoplastic Agents
  • Carcinogens
  • DNA-Binding Proteins
  • MM 11254
  • MM 11365
  • Ornithine Decarboxylase Inhibitors
  • RARA protein, human
  • RNA, Messenger
  • Rara protein, mouse
  • Rara protein, rat
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoids
  • Transcription Factor AP-1
  • Transcription Factors
  • ZNF148 protein, human
  • Zfp148 protein, mouse
  • Znf148 protein, rat
  • retinoic acid receptor gamma
  • 9,10-Dimethyl-1,2-benzanthracene
  • Protein Kinases
  • Collagenases
  • Tetradecanoylphorbol Acetate