RAR AND RXR SELECTIVE LIGANDS COOPERATIVELY INDUCE APOPTOSIS AND NEURONAL DIFFERENTIATION IN P19 EMBRYONAL CARCINOMA-CELLS

Retinoids cause differentiation in embryonal carcinoma (EC) cells, thu s mimicking events in mammalian development, Here, we show that retino ids also cause apoptosis in P19 EC cells, Characteristic DNA fragmenta tion was observed within 36 h after addition of retinoic acid (RA), Sy nthetic retinoids that are selective for RA receptors (RAR) were also effective in inducing apoptosis, whereas RXR selective ligands were wi thout effect, The combination of RAR and RXR ligands resulted in a syn ergistic increase in apoptotic cell death, As with apoptosis, neuronal differentiation of P19 cells was synergistically induced by the combi nation of RAR and RXR ligands. Data obtained with an RAR antagonist an d with P19 cells carrying a dominant negative RXR indicate that the tw o processes are receptor mediated, Together, our results indicate that retinoid-induced apoptosis and neuronal differentiation are closely c oupled, and that both RAR and RXR play a role in these processes as ac tive receptors for their respective ligands.