Glucocorticoid and phorbol ester effects in 3T3-L1 fibroblasts suggest multiple and previously undescribed mechanisms of glucocorticoid receptor-AP-1 interaction.
A number of mechanisms have been proposed to account for glucocorticoid hormone and mitogen effects observed on the transcription of engineered exogenous target genes. However, the effect of the co-addition of these agents on the full range of endogenous responsive genes in a given cell type has not been addressed. We detected 19 metabolically labeled proteins or in vitro translation products whose synthesis was altered in 3T3-L1 fibroblasts in response to glucocorticoid hormone using two-dimensional electrophoresis on large-format gels. Co-addition of the mitogenic phorbol ester, tetradecanoylphorbolacetate (TPA), with glucocorticoid hormone resulted in independent (one species), synergistic (six species), and antagonistic (five species) effects on the glucocorticoid regulation of individual gene products, while seven other glucocorticoid regulated species were not affected. These and additional observations suggest direct and gene-specific effects of glucocorticoid receptor and AP-1 on the transcription of responsive genes, and for some of these genes the pattern of regulation is not accounted for by mechanisms described to date. In addition, the pattern of regulation of five species is consistent with a role in mediating the opposing physiological effects of glucocorticoid hormone and growth factors in these cells.
Wheeler
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E. Henry Keutmann Laboratory, Endocrine-Metabolism Unit, University of Rochester Medical Center, NY 14642.
Sadowski
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Young
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D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010703:Phorbol Esters / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D005938:Glucocorticoids; D010703:Phorbol Esters; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate