BMP4-INDUCED AND RA-INDUCED APOPTOSIS IS MEDIATED THROUGH THE ACTIVATION OF RETINOIC ACID RECEPTOR-ALPHA AND RECEPTOR-GAMMA IN P19 EMBRYONAL CARCINOMA-CELLS

Some growth factors, for example, members of the transforming growth f actor-p family, can induce apoptosis in a variety of cells. Retinoic a cid (RA) also causes apoptosis in several malignant cell types. We hav e previously demonstrated that, although BMP2 or BMP4 cannot induce ap optosis alone, BMP2 or BMP4 and RA synergize to induce apoptosis in 95 % of P19 embryonal carcinoma cells within 4 days of treatment. Such tr eatment also prevents neuronal differentiation of these cells. Retinoi ds exert their many effects through any of six distinct nuclear recept ors. These retinoid-activated transcription factors directly regulate genes involved in cellular responses such as apoptosis. Complete under standing of how BMP and RA specifically induce cell death requires ide ntification of the retinoid receptors controlling apoptosis. By using receptor-selective retinoid agonists and antagonists, we have obtained evidence suggesting that activation of RAR alpha or gamma is sufficie nt to induce apoptosis in BMP4-treated cells. (C) 1998 Academic Press.