RECEPTOR-SELECTIVE RETINOIDS IMPLICATE RETINOIC ACID RECEPTOR-ALPHA AND RECEPTOR-GAMMA IN THE REGULATION OF BMP-2 AND BMP-4 IN F9 EMBRYONALCARCINOMA-CELLS

The effect of retinoids on malignant cells and embryos indicates that retinoids influence the expression of growth factors or alter the resp onse of cells to growth factors. The bone morphogenetic proteins, Bmp- P and Bmp-4, are candidates for such growth factors because retinoic a cid (RA) treatment of F9 embryonal carcinoma cells induced Bmp-2 mRNA, while simultaneously repressing Bmp-4 levels, Also, recombinant Bmp-2 affected the growth and differentiation of these cells, Regulation of each gene was concentration dependent and required continuous RA trea tment, The short half-lives of the Bmp-2 (75 +/- 11 min) and Bmp-4 (70 +/- 4 min) mRNAs suggest that their abundance is primarily controlled at the transcriptional level, To determine which RA receptor (RAR) co ntrols bmp-2 and bmp-4 expression, F9 cells were exposed to various re ceptor-selective retinoids, RAR alpha- and gamma-selective retinoids i nduced Bmp-2 and repressed Bmp-4 equally as well as all-trans RA. In c ontrast, a RAR beta-selective retinoid had little effect on Bmp-2 indu ction but repressed Bmp-4. A RAR alpha-selective antagonist inhibited all-trans RA stimulation of Bmp-2, although not as dramatically as a R AR beta gamma-selective antagonist, No differences were observed betwe en Bmp levels in all-trans RA and 9-cis RA-treated cells, indicating t hat the RXRs play little part in controlling these genes, The results are consistent with RAR alpha and gamma-controlled Bmp-2 and Bmp-4 reg ulation.