Retinoic acid is a negative regulator of AP-1-responsive genes.
We present evidence that retinoic acid can down-regulate transcriptional activation by the nuclear protooncogene c-jun. All three members of the retinoic acid receptor (RAR) subfamily (RAR alpha, RAR beta, and RAR gamma) can repress transcriptional induction of the human collagenase gene or a heterologous promoter that contains the collagenase promoter AP-1-binding site. In contrast, the retinoid X receptor fails to repress Jun/AP-1 activity, demonstrating a significant difference between the two regulatory systems through which retinoids exert their transcriptional control. Analysis of RAR alpha mutants in transfection studies reveals that the DNA-binding domain is important for the inhibition of Jun/AP-1 activity, even though the RAR does not bind the collagenase AP-1 site. Rather, gel-retardation assays reveal that bacterially expressed full-length RAR alpha inhibits binding of Jun protein to target DNA. These data suggest that the RAR alpha may form a nonproductive complex with c-Jun and provides a simple mechanisms by which retinoic acid may limit cell growth and possibly malignant progression.
Schüle
R
R
Howard Hughes Medical Institute, La Jolla, CA.
Rangarajan
P
P
Yang
N
N
Kliewer
S
S
Ransone
L J
LJ
Bolado
J
J
Verma
I M
IM
Evans
R M
RM
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006367:HeLa Cells / Q000502:physiology; D003012:Microbial Collagenase / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases; D003012:Microbial Collagenase