Receptor-selective retinoids implicate retinoic acid receptor alpha and gamma in the regulation of bmp-2 and bmp-4 in F9 embryonal carcinoma cells.
The effect of retinoids on malignant cells and embryos indicates that retinoids influence the expression of growth factors or alter the response of cells to growth factors. The bone morphogenetic proteins, Bmp-2 and Bmp-4, are candidates for such growth factors because retinoic acid (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 treatment. 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) controls bmp-2 and bmp-4 expression, F9 cells were exposed to various receptor-selective retinoids. RAR alpha- and gamma-selective retinoids induced Bmp-2 and repressed Bmp-4 equally as well as all-trans RA. In contrast, a RAR beta-selective retinoid had little effect on Bmp-2 induction but repressed Bmp-4. A RAR alpha-selective antagonist inhibited all-trans RA stimulation of Bmp-2, although not as dramatically as a RAR beta gamma-selective antagonist. No differences were observed between Bmp levels in all-trans RA and 9-cis RA-treated cells, indicating that the RXRs play little part in controlling these genes. The results are consistent with RAR alpha and gamma-controlled Bmp-2 and Bmp-4 regulation.
Rogers
M B
MB
Department of Biology, University of South Florida, Tampa 33620, USA. rogers@chuma.cas.usf.edu
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015152:Blotting, Northern; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D003994:Bucladesine / Q000494:pharmacology; D054278:Embryonal Carcinoma Stem Cells; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006133:Growth Substances / Q000235:genetics*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
D001565:Benzoates; D019485:Bone Morphogenetic Proteins; D003994:Bucladesine; D006133:Growth Substances; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D013806:Theophylline; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C068073:Am 580