cAMP signaling can antagonize potent glucocorticoid post-transcriptional inhibition of stanniocalcin gene expression.
Stanniocalcin (STC) is a glycoprotein hormone first discovered in fish as a homeostatic regulator of calcium and phosphate transport; it has recently been discovered in mammals, in which it appears to have a similar role. It has also been implicated in a number of different physiological processes through correlative studies, but the factors regulating its production have not been elucidated. In this report, we show that steady-state STC mRNA levels in the mouse corticotrope tumor line, AtT-20, were exquisitely sensitive to glucocorticoids. Hydrocortisone and dexamethasone (Dex) induced a dramatic reduction in steady-state STC mRNA levels in AtT-20 cells through a post-transcriptional mechanism. Similarly, glucocorticoids down-regulated STC mRNA levels in the human fibrosarcoma cell line, HT1080. The specificity of the glucocorticoid-mediated decrease in STC mRNA abundance was shown using the glucocorticoid receptor antagonist, RU-486. Activation of the cAMP-signaling pathway in glucocorticoid-cultured AtT-20 cells transiently restored STC gene expression. Treatment of AtT-20 cells with the transcriptional inhibitor, actinomycin D, rescued steady-state STC mRNA levels from Dex-induced repression, indicating that the Dex-mediated decrease in STC gene expression requires current gene transcription. Taken together, these results describe a unique model system in which cAMP-stimulated events can reverse post-transcriptional repression of gene expression by glucocorticoids.
Groves
T C
TC
Department of Oncology, The University of Western Ontario and London Regional Cancer Centre, London, Ontario, Canada.
Wagner
G F
GF
DiMattia
G E
GE
D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D003470:Culture Media; D000242:Cyclic AMP / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology*; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006728:Hormones / Q000096:biosynthesis* / Q000235:genetics; D006854:Hydrocortisone / Q000494:pharmacology; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015398:Signal Transduction
D003470:Culture Media; D005938:Glucocorticoids; D006023:Glycoproteins; D006728:Hormones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C051795:teleocalcin; D003907:Dexamethasone; D000242:Cyclic AMP; D006854:Hydrocortisone