Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation is associated in some tissues with diminished responsiveness to steroid hormone action. We hypothesized that proinflammatory cytokines alter steroid hormone sensitivity, in part, by reducing levels of key nuclear receptor coactivators. Treatment of cultured human uterine smooth muscle cells (UtSMC) with TNF-alpha significantly reduced mRNA for the coactivators, SRC-1 (42%, P<0.01) and 2 (47%, P<0.03), and diminished the respective protein levels, but did not significantly alter the mRNAs encoding SRC-3, CBP and the corepressors, NCoR and SMRT; or progesterone receptor protein levels. To assess TNF-alpha effects on steroid hormone-mediated transcriptional activity, UtSMC were transfected with progesterone receptor B (PR-B) and a model PRE2-luciferase reporter construct. Transfected UtSMC were treated with progesterone alone or in the presence of TNF-alpha, and assayed for luciferase activity. TNF-alpha (10 ng/ml) diminished progesterone-stimulated PR-B-mediated transactivation by approximately 60% (P<0.02). The TNF-alpha-dependent decrease in PRE-luciferase activity was fully prevented by cotransfection with SRC-2, and partially prevented with exogenous SRC-1. In conclusion, TNF-alpha impairs progesterone-stimulated PR-B-mediated transactivation, and these effects appear to be due, in part, to reduced expression of SRC-1 and -2, which is a novel mechanism by which inflammation can functionally block steroid hormone action.
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PMID:Tumor necrosis factor-alpha suppresses the expression of steroid receptor coactivator-1 and -2: a possible mechanism contributing to changes in steroid hormone responsiveness. 1523 21

Both agonist- and antagonist-bound glucocorticoid receptors (GRs) and progesterone receptors (PRs) regulate gene transcription with the assistance of corepressors (NCoR and SMRT) and coactivators (TIF2/GRIP1, SRC1, and AIB1). Receptor binding of these cofactors is competitive and is considered to involve interactions between the C-terminal ligand binding domain of receptors and receptor interaction domains (RIDs) in the middle and C-terminus of coactivators and corepressors, respectively. Therefore, our recent finding that an amino terminal fragment of TIF2 (TIF2.0 = amino acids 1-627) competed for GR and PR interactions with corepressors in mammalian two-hybrid assays was unexpected. Here, we use biochemical approaches (mammalian two-hybrid, pull-down, and coimmunoprecipitation assays) to locate an N-terminal GR region that is sufficient to bind TIF2.0. In contrast, an N-terminal sequence of PR-B that is largely missing in the shorter PR-A is necessary but not sufficient for TIF2.0 binding. Mutagenesis studies of NCoR establish that the more amino-terminal RID#1, but not RID#2, is necessary for binding to both GR and PR agonist and antagonist complexes. ChIP assays indicate that PR and NCoR each selectively localize to the enhancer element (PRE) of a transiently transfected PREtkLUC reporter in the presence of antagonist steroid, whereas exogenous TIF2.0 reduces the amount of PRE-associated NCoR. Importantly, exogenous TIF2.0 also inhibits the biological responses to added NCoR under the same conditions as those used in the ChIP assays. These results suggest that both N-terminal and middle sequences of TIF2 participate in competing with corepressor for regulating the gene transcriptional responses of GRs and PRs.
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PMID:Amino-terminal domain of TIF2 is involved in competing for corepressor binding to glucocorticoid and progesterone receptors. 1757 60