Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform: A mechanism for the generation of glucocorticoid resistance
Autor: | Robert H. Oakley, John A. Cidlowski, Christine M. Jewell, Jeffrey C. Webster |
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Rok vydání: | 2001 |
Předmět: |
Gene isoform
Drug Resistance Biology Proinflammatory cytokine Receptors Glucocorticoid Glucocorticoid receptor Gene expression Animals Humans Protein Isoforms RNA Messenger Receptor Glucocorticoids Regulation of gene expression Multidisciplinary Tumor Necrosis Factor-alpha NF-kappa B Biological Sciences NFKB1 Molecular biology Gene Expression Regulation COS Cells Cytokines Tumor necrosis factor alpha HeLa Cells Interleukin-1 |
Zdroj: | Proceedings of the National Academy of Sciences. 98:6865-6870 |
ISSN: | 1091-6490 0027-8424 |
DOI: | 10.1073/pnas.121455098 |
Popis: | Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kappaB and the glucocorticoid receptor (GR). The human glucocorticoid receptor (hGR) gene encodes two protein isoforms: a cytoplasmic alpha form (GRalpha), which binds hormone, translocates to the nucleus, and regulates gene transcription, and a nuclear localized beta isoform (GRbeta), which does not bind known ligands and attenuates GRalpha action. We report here the identification of a tumor necrosis factor (TNF)-responsive NF-kappaB DNA binding site 5' to the hGR promoter that leads to a 1.5-fold increase in GRalpha mRNA and a 2.0-fold increase in GRbeta mRNA in HeLaS3 cells, which endogenously express both GR isoforms. However, TNF-alpha treatment disproportionately increased the steady-state levels of the GRbeta protein isoform over GRalpha, making GRbeta the predominant endogenous receptor isoform. Similar results were observed following treatment of human CEMC7 lymphoid cells with TNF-alpha or IL-1. The increase in GRbeta protein expression correlated with the development of glucocorticoid resistance. |
Databáze: | OpenAIRE |
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