Nerve growth factor activates the RAR beta 2 promoter by a Ras-dependent mechanism

Nerve growth factor (NGF) and retinoic acid (RA) exert important actions on PC12 cells. We have previously shown that incubation with NGF induces reti noic acid receptor beta (RAR beta) binding to a hormone response element in PC12 cells. in this study we show that NGF increases RAR beta protein leve ls by enhancing basal RAR beta2 promoter activity, and potentiates stimulat ion by RA in transient transfection assays. The effect of RA is mediated by a RA response element (RARE) located at -37/-53 and mutation of this eleme nt abolishes activation by the retinoid, as well as cooperation with NGF. H owever, the action of NGF is independent of the RARE and is mediated by seq uences overlapping the TATA box and the INR comprising nucleotides -59 to 14. NGF produces a strong decrease in some of the complexes that bind to th e INR. These results suggest that the RAR beta2 gene could be in a basal re pressed state and NGF could increase RAR beta2 transcription by inducing th e release of some inhibitory factors from the INR. Functional Ras is requir ed for RAR beta2 promoter activation by NGF because expression of oncogenic Ras increases promoter activity and a dominant inhibitory Ras mutant block s the effect of NGF. Oncogenic Raf also mimics the effect of NGF on the pro moter. Other ligands of tyrosine kinase receptors that stimulate Ras also c ause RAR beta2 promoter activation and act cooperatively with RA. These res ults indicate the existence of cross-coupling of the Ras-Raf signal transdu ction pathway with retinoid receptor pathways which could increase sensitiv ity to RA and be important for PC12 cell function.