title: Regulation of retinoic acid-induced inhibition of AP-1 activity by orphan receptor chicken ovalbumin upstream promoter-transcription factor.
abstract: Retinoids are therapeutically effective in the treatment of various cancers, and some of the therapeutic action of retinoids can be ascribed to their potent inhibition of AP-1 activity that regulates transcription of genes associated with cell growth. We recently reported that the expression of orphan receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) plays a role in mediating the growth inhibitory effect of trans-retinoic acid (trans-RA) in cancer cells. To gain insight into the molecular mechanism by which COUP-TF regulates trans-RA activity, we evaluated the effect of COUP-TF on antagonism of AP-1 activity by trans-RA. Our results demonstrated a positive correlation between COUP-TF expression and the ability of trans-RA to inhibit AP-1 activity in various cancer cell lines. In transient transfection assay, expression of COUP-TF strongly inhibited tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 transactivation activity and transactivation of c-Jun/c-Fos in both a trans-RA-dependent and -independent manner. In vitro studies demonstrated that the addition of COUP-TF inhibited c-Jun DNA binding through a direct protein-protein interaction that is mediated by the DNA binding domain of COUP-TF and the leucine zipper of c-Jun. Stable expression of COUP-TF in COUP-TF-negative MDA-MB231 breast cancer cells restored the ability of trans-RA to inhibit 12-O-tetradecanoylphorbol-13-acetate-induced c-Jun expression. The effect of COUP-TF in enhancing the trans-RA-induced antagonism of AP-1 activity required expression of retinoic acid receptors (RARs), since stable expression of COUP-TF in COUP-TF-negative HT-1376 bladder cancer cells, which do not express RARalpha and RARbeta, failed to restore trans-RA-induced AP-1 repression. Thus, COUP-TF, through its physical interaction with AP-1, promotes anticancer effects of retinoids by potentiating their anti-AP-1 activity.
authors.affiliation: Burnham Institute, Cancer Center, La Jolla, California 92037, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Kolluri
authors.forename: Guo-quan
authors.initials: GQ
authors.lastname: Chen
authors.forename: Xiao-kun
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D051836:COUP Transcription Factors; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016350:Leucine Zippers; D008024:Ligands; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; D008024:Ligands; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D012176:Retinoids; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014212:Tretinoin; D004247:DNA; D005982:Glutathione Transferase; D013755:Tetradecanoylphorbol Acetate