SPECIFIC INDUCTION OF APOPTOSIS IN P19 EMBRYONAL CARCINOMA-CELLS BY RETINOIC ACID AND BMP2 OR BMP4

Retinoic acid (RA) affects the response of many cells to growth factor s, including the bone morphogenetic proteins (BMPs). The BMPs are memb ers of the TGF-beta family of growth factors, originally identified by their bone-inducing activities. Their widespread expression suggests many roles other than that in osteogenesis. Because RA modulates the c ell's response to growth factors, this may be a means by which the ret inoids exert some of their known teratogenic effects, One such cellula r response may be apoptosis. While apoptosis is required for normal de velopment, the location and timing of its induction must be carefully controlled, Recently, several TGF-beta family members have been implic ated in the induction of apoptosis in certain cell types. We shaw here , using P19 embryonal carcinoma cells, that the combination of RA and BMP2 or BMP4 synergistically induces apoptosis in 40% of the populatio n within 24 hr. In contrast, RA alone induces apoptosis in only 10-15% of the population and each of the BMPs alone minimally induces apopto sis. Apoptosis depends on the dose of both the RA and the BMP as well as on new protein synthesis. Further, tile induction of apoptosis prev ents the formation of fully differentiated neurons and glial cells and instead leads to primarily smooth muscle cell differentiation. These results suggest that some of the malformations caused by retinoids may be due to the induction of inappropriate apoptosis in cells exposed t o BMPs. (C) 1996 Academic Press, Inc.