Unique anti-activator protein-1 activity of retinoic acid receptor beta

The anticancer effects of retinoids are mainly mediated by two classes of n uclear receptors, the retinoic acid receptors (RARs) and retinoid ii recept ors (RSRs), which are encoded by three distinct genes (alpha, beta, and gam ma). Recent studies have demonstrated that RAR beta plays a critical role i n mediating anticancer effects of retinoids. However, how RAR beta exerts i ts potent anticancer effects remains largely unknown. In this study, we inv estigated anti-Activator Protein-1 (AP-I) activity of RAR beta. In a transi ent transfection assay, all three RAR subtypes, RAR alpha, RAR beta, and RA R gamma could effectively inhibit phorbol ester 12-O-tetradecanoylphorbol-1 3-acetate-induced AP-I activity and the activity of oncogenes c-Jun and c-F os on AP-1 containing reporter genes in the presence of retinoic acid (EU). However, RAR beta showed a strong EU-independent inhibition of AP-I activi ty, whereas inhibition of AP-I activity by RAR alpha and RAR gamma was RA d ependent. By using several hybrid receptors that contain either the COOH-te rminal portion or the NH2-terminal portion of RRP, we demonstrated that the NH2-terminal portion of RAR beta, the A/B domain, was mainly responsible f or the RA-independent inhibition of AP-1 activity. This activity was not at tributable to constitutive AF-1 activity of RAR beta, because it did not ac tivate several RA response element-containing reporter genes. In addition, inhibition of histone deacetylase activity by trichostatin A did not overco me the inhibitory effect of RAR beta. In cancer cells, stable transfection of RAR beta exhibited strong inhibition of AP-I activity, even in the absen ce of IU. Moreover, expression of endogenous AP-1-responsive gene collagena se I was strongly repressed in cancer cells stably transfected with RAR bet a. In studying the antitransforming activity of RAR beta, we observed that the growth of breast cancer MDA-MB231 cells in soft agar was significantly repressed in a RA-independent manner when cells were stably transfected wit h RAR beta but not RAR alpha. Together, our results demonstrate that RAR be ta may exert its potent anticancer effect in part through its unique anti-A P-1 activity.