Antagonism between retinoic acid receptors and AP-1: implications for tumor promotion and inflammation.
Retinoids such as retinoic acid (RA) are potent anti-arthritic and anti-neoplastic agents. We investigated the mechanism by which RA inhibits induction of collagenase gene transcription by inflammatory mediators, tumor promoters, and proto-oncogenes. We found that the RA receptors (RARs) are potent inhibitors of AP-1 activity generated either by cJun homodimers or cJun/cFos heterodimers. In addition, both cJun and cFos can inhibit RAR activity. In vitro experiments suggested that this inhibition is due to an interaction between RAR and AP-1 proteins that results in mutual loss of DNA-binding activity. The RARs need not bind to the AP-1 site, neither does AP-1 bind to RA response elements. An understanding of this antagonism between the RAR and AP-1 might help to elucidate the anti-neoplastic and anti-arthritic effects of RA as well as its effects on cell differentiation and proliferation.
Yang-Yen
H F
HF
Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla 92093.
Zhang
X K
XK
Graupner
G
G
Tzukerman
M
M
Sakamoto
B
B
Karin
M
M
Pfahl
M
M
D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D003012:Microbial Collagenase / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology*; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D018168:Receptors, Retinoic Acid; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
D002352:Carrier Proteins; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D004247:DNA; D003012:Microbial Collagenase