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 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.
Dawson
M I
MI
Molecular Medicine Research Institute, Mountain View, CA 94043, USA. mdawson@mmrx.org
Park
J H
JH
Chen
G
G
Chao
W
W
Dousman
L
L
Waleh
N
N
Hobbs
P D
PD
Jong
L
L
Toll
L
L
Zhang
X
X
Gu
J
J
Agadir
A
A
Merchant
J L
JL
Bai
L
L
Verma
A K
AK
Thacher
S M
SM
Chandraratna
R A
RA
Shroot
B
B
Hill
D L
DL
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
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