The anti-progestin RU486 stabilizes the progestin-induced fatty acid synthetase mRNA but does not stimulate its transcription.
Progestins induce fatty acid synthetase (FAS) in breast cancer cell lines, both increasing its gene transcription and mRNA stabilization (Joyeux, C., Rochefort, H., and Chalbos, D. (1989) Mol. Endocrinol. 4, 681-686). In vitro run-on transcription assays show that RU486, in contrast to progestin, inhibits FAS transcription by 40-50%. Moreover and surprisingly, anti-progestin RU486 also stabilizes FAS mRNA 3- to 4-fold in MCF7 cells as measured by chase experiments in the presence of actinomycin D or cordycepin or after short cell labeling with [3H]uridine. Dexamethasone is inefficient in increasing the half-life of FAS mRNA in MCF7 cells. RU486 had no effect on MDA-MB 231 cells which contain glucocorticoid but no progesterone receptors, indicating that the progesterone receptor is implicated in this regulation. RU486-induced mRNA stabilization allows delayed accumulation of FAS mRNA. These results indicate that the progesterone receptor can be activated separately to stimulate gene transcription or stabilize mRNA.
Chalbos
D
D
Institut National de la Santé et de la Recherche Médicale U 148, Unit-Hormones and Cancer, Montpellier, France.
Galtier
F
F
Emiliani
S
S
Rochefort
H
H
D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D011372:Progestins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D011372:Progestins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D003609:Dactinomycin; D015735:Mifepristone; D003907:Dexamethasone; D064429:Fatty Acid Synthases; C058120:cordycepin