RETINOIC ACID REGULATES ORNITHINE DECARBOXYLASE GENE-EXPRESSION AT THE TRANSCRIPTIONAL LEVEL

Retinoic acid (RA) is important for normal mammalian development and g rowth. Ornithine decarboxylase (ODC) is the first and rate-limiting en zyme in the biosynthesis of the polyamines, and we have previously sho wn that ODC mRNA levels are suppressed by RA in human skin cells. Usin g HeLa cells, we now show that treatment with 0.5 muM RA for 24 h supp resses endogenous ODC mRNA levels and the expression of a transfected ODC/chloramphenicol acetyltransferase plasmid (Kpn-ODCCAT), containing sequences from - 1450 to + 810 of the human ODC gene. Co-transfection with either the alpha-RA receptor (alpha-RAR) or a chimeric a-RA/oest rogen receptor (alpha-RAER) followed by treatment with the cognate hor mone suppresses expression of Kpn-ODCCAT and Not-ODCCAT, which contain s sequences from - 250 to + 514. Liganded alpha-RAR suppresses the act ivity of Kpn-ODCCAT more markedly than does liganded alpha-RAER (98 % and 80 % suppression, respectively), whereas both receptors have very similar effects on Not-ODCCAT expression (73 % and 67 % suppression, r espectively). The unliganded alpha-RAR suppresses Kpn-ODCCAT by 76%, w hereas unliganded alpha-RAER has no significant effect. These data sho w that RA regulates ODC-gene expression at the transcriptional level, and that alpha-RAR, but not alpha-RAER, can confer full hormonal respo nsiveness. This suggests that the activating function present in the a lpha-RAR ligand-binding domain is required for full transcriptional re gulation.