Modulation of glucocorticoid-regulated transcription by purines: novel characteristics and implications for tissue specificity of steroid responses.
Treatment of the T47D(A1-2) mammary carcinoma cell line with the nonspecific kinase inhibitor 2-aminopurine (2AP) has an unusual effect on induction of the mouse mammary tumor virus promoter by glucocorticoids. 2AP initially abrogates the dexamethasone-mediated increase, but after about 16-20 h, this effect is reversed, and continued incubation with 2AP potently stimulates the hormone induction. The biphasic kinetics of 2AP action displayed cell specificity. No inhibitory phase was seen in fibroblasts. Cell type specificity is also seen upon treatment of cells with isobutylmethylxanthine (IBMX). Dexamethasone action is inhibited in mammary cells, but potentiated in fibroblasts. Unlike 2AP treatment, IBMX continues to suppress the hormone response through at least 48 h of treatment. IBMX is commonly used as a phosphodiesterase inhibitor, and indeed, it stimulates a cAMP-dependent promoter in both mammary carcinoma cells and fibroblasts. Because elevating cAMP will potentiate dexamethasone-mediated induction in mammary cells, IBMX must be interventing in another pathway that elicits IBMX-dependent suppression of the hormone response. Pharmacological studies suggest that this interaction is not mediated through adenosine receptors, histamine receptors, or imidazoline receptors. The five-member imidazole ring plays a critical role in the suppressive activity; substitutions at the 7 position inhibit suppression. These results give further indication of coupling of steroid receptor action to other cellular signaling pathways. This complex spectrum of interactions may play a central determining role in the tissue specificity of the response to steroid hormones.
Nordeen
S K
SK
Department of Pathology, University of Colorado Health Sciences Center, Denver 80262.
Moyer
M L
ML
Bona
B J
BJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000502:physiology*; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D011687:Purines / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000631:Aminopyridines; D005938:Glucocorticoids; D011687:Purines; D015056:1-Methyl-3-isobutylxanthine; C032439:alpha-aminopyridine