Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ligand-dependent interaction of nuclear receptors and coactivators is a critical step in nuclear receptor-mediated transcriptional regulation. TR-binding protein (TRBP) interacts with nuclear receptors through a single LXXLL motif. Evidence suggested that the sequences flanking the LXXLL motif in a number of coactivators determine receptor selectivity. We performed mutagenesis studies at residues adjacent to the TRBP LXXLL motif and identified S884 of TRBP at the -3 position of the LXXLL motif as a key residue for receptor selectivity. Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERbeta, TR, and RXR vs. ERalpha. Transient transfection studies further confirmed that the LXXLL-binding affinity correlates with TRBP transcriptional activity. Consistent with the structural modeling, an E380G substitution within ERalpha altered the binding to TRBP mutants, demonstrating the direct contact between TRBP S884 and ERalpha E380, which is a residue that distinguishes receptor subclasses. Furthermore, S884 can be phosphorylated by MAPK in vitro, an event that significantly altered the binding of TRBP to ER and suggests a potential mechanism for regulatory interaction. As the differential recruitment of TRBP to ERalpha and ERbeta may rely on S884, our finding provides insight into estrogen signaling and may lead to the development of therapeutic receptor-selective peptide antagonists.
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PMID:Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs. 1177 44

Mast cells, platelets, and some macrophages are abundant sources of PGD(2) and its active metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)). The lipid mediator 15-d-PGJ(2) regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ(2) has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-alpha, IL-1beta, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Data concerning the effects of 15-d-PGJ(2) on human T cells and immune regulation are sparse. IL-8, a cytokine with both chemotactic and angiogenic effects, is produced by T lymphocytes following activation. Whether 15-d-PGJ(2) can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ(2) treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ(2) does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ(2) induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ(2) did not occur through the nuclear receptor PPAR-gamma, as synthetic PPAR-gamma agonists did not mimic the IL-8-inducing effects of 15-d-PGJ(2). The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-kappaB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ(2) can act as a potent proinflammatory mediator in activated T cells by inducing the production of IL-8. These findings show the complexity with which 15-d-PGJ(2) regulates T cells by possessing both pro- and anti-inflammatory properties depending on the activation state of the cell. The implications of this research also include that caution is warranted in assigning a solely anti-inflammatory role for 15-d-PGJ(2).
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PMID:15-deoxy-Delta 12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway. 1180 78

Retinoid X receptor alpha (RXRalpha) has emerged as an important nuclear receptor involved in hepatocarcinogenesis, because its ligand suppresses the development of hepatocellular carcinoma (HCC) in both experimental and clinical studies. We have demonstrated that phosphorylation of RXRalpha at serine 260 interferes with its function and delays its degradation in cultured human HCC, leading to enhanced cellular proliferation. Here, we show that in normal liver and in nonproliferating hepatocyte cultures, RXRalpha is unphosphorylated and highly ubiquitinated, rendering it sensitive to proteasome-mediated degradation. On the other hand, phosphoserine 260 RXRalpha is resistant to ubiquitination and proteasome-mediated degradation in both human HCC tissues and a human HCC cell line, HuH7. In these tissues and cells, serine 260 is phosphorylated by mitogen-activated protein (MAP) kinase. In proliferating normal hepatocytes, similar to HCC cells, RXRalpha is also phosphorylated at serine 260 and resistant to ubiquitin-mediated degradation by proteasome, but this ubiquitination of RXRalpha is differentially regulated between HCC cells and normal hepatocytes. In proliferating hepatocytes, 9-cis retinoic acid (9cRA), a ligand to RXRalpha, suppresses MAP kinase-mediated phosphorylation and thereby enhances ubiquitination of RXRalpha, whereas it fails to exert these effects in HCC cells. In conclusion, switching of the ubiquitin/proteasome-dependent degradation of RXRalpha by phosphorylation at serine 260 may be responsible for the aberrant growth of HCC and its suppression by retinoids.
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PMID:Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma. 1182 6

The prostaglandin, 15-deoxy Delta(12,14)-prostaglandin J2 (15d-PGJ2)(1), and thiazolidinediones are ligands for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, which mediates anti-inflammatory activity by suppressing murine macrophage (Mphi) production of the inflammatory mediator, nitric oxide (NO). Here, we elucidated this anti-inflammatory activity further by investigating whether PPAR-gamma ligands regulated a panel of proinflammatory and anti-inflammatory cytokines produced by primary inflammatory murine Mphi (thioglycollate-elicited peritoneal exudate Mphi; PEM). Thiazolidinediones and 15d-PGJ2 suppressed lipopolysaccharide (LPS)-induced PEM production of NO and IL-12(p40) to a greater extent than IL-6 and TNF-alpha production. Whereas 15d-PGJ2 showed the greatest extent of suppression of proinflammatory mediator production, the thiazolidinedione, BRL49653, was the most potent compound studied. Surprisingly, treatment with the Mphi-activation cytokine, IFN-gamma, prevented PPAR-gamma ligands from suppressing the proinflammatory cytokines completely and reduced their suppression of NO production substantially, demonstrating that activation conditions affect PPAR-gamma-mediated, anti-inflammatory activity. Western analysis demonstrated that the antagonistic activity of IFN-gamma did not involve modulation of PPAR-gamma expression but showed that IFN-gamma interfered with PPAR-gamma ligand regulation of p42/p44 MAP kinase activation and the cytosolic disappearance of NF-kappaB upon LPS stimulation. Finally, we showed that PPAR-gamma ligands did not substantially modulate production of the anti-inflammatory cytokine, IL-10, and that antibody-mediated neutralization of IL-10 did not prevent the ligands from suppressing proinflammatory mediator production. In contrast to studies with noninflammatory human monocytes and Mphi, our results demonstrate that primary murine inflammatory Mphi are extremely sensitive to the anti-inflammatory activity of PPAR-gamma ligands. These results suggest that drugs such as thiazolidinediones may be most effective in suppressing Mphi activity early (i.e., in the absence of lymphocyte-derived IFN-gamma) in the inflammatory process.
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PMID:Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by IFN-gamma. 1192 55

The present study using immunoblot showed that corticosterone (B) could induce a rapid activation of p38 in PC12 cells. The dose and time response curves w ere bell shaped with a maximal activation at 10-9 mol/L and 15 min respectively. The activation was not affected by steroid nuclear receptor antagonist RU38486. Bovine serum albumin coupled B (B-BSA) could induce phosphorylation of p38. Tyrosine kinase inhibitor genistein failed to block the phosphorylation, a fact suggesting that the tyrosine kinase activity is not involved in the pathway. On the other hand, phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, could mimic the actions of B, while G 6976, a PKC inhibitor, could completely abolish the phosphorylation induced by B. These results clearly demonstrate that B activates p38 MAPK readily via a putative membrane receptor through a PKC-dependent pathway.
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PMID:Rapid activation of p38 mitogen-activated protein kinase by corticosterone in PC12 cells. 1193 Feb 17

1 alpha,25(OH)(2)D(3) and 24R,25(OH)(2)D(3) mediate their effects on chondrocytes and osteoblasts in part through increased activity of protein kinase C (PKC). For both cell types, 1 alpha,25(OH)(2)D(3) exerts its effects primarily on more mature cells within the lineage, whereas 24R,25(OH)(2)D(3) exerts its effects primarily on relatively immature cells. Studies using the rat costochondral cartilage growth plate as a model indicate that the two metabolites increase PKC activity by different mechanisms. In growth zone cells (prehypertrophic/upper hypertrophic cell zones), 1 alpha,25(OH)(2)D(3) causes a rapid increase in PKC that does not involve new gene expression. 1 alpha,25(OH)(2)D(3) binds its membrane receptor (1,25-mVDR), resulting in activation of phospholipase A(2) and the rapid release of arachidonic acid, as well as activation of phosphatidylinositol-specific phospholipase C, resulting in formation of diacylglycerol and inositol-1,4,5-tris phosphate (IP(3)). IP(3) leads to release of intracellular Ca(2+) from the rough endoplasmic reticulum, and together with diacylglycerol, the increased Ca(2+) activates PKC. PKC is then translocated to the plasma membrane, where it initiates a phosphorylation cascade, ultimately phosphorylating the extracellular signal-regulated kinase-1 and -2 (ERK1/2) family of MAP kinases (MAPK). PKC increases are maximal at 9 min, and MAPK increases are maximal at 90 min in these cells. By contrast, 24R,25(OH)(2)D(3) increases PKC through activation of phospholipase D in resting zone cells. Peak production of diacylglycerol via phospholipase D2 is at 90 min, as are peak increases in PKC. Some of the effect is direct on existing plasma membrane PKC, but most is due to new PKC expression; translocation is not involved. Arachidonic acid and its metabolites also play differential roles in the mechanisms, stimulating PKC in growth zone cells and inhibiting PKC in resting zone cells. 24R,25(OH)(2)D(3) decreases phospholipase A(2) activity and prostaglandin production, thereby overcoming this potential inhibitory component, which may account for the delay in the PKC response. Ultimately, ERK1/2 is phosphorylated. PKC-dependent MAPK activity transduces some, but not all, of the physiological responses of each cell type to its respective vitamin D metabolite, suggesting that the membrane receptor(s) and nuclear receptor(s) may function interdependently to regulate proliferation and differentiation of musculoskeletal cells, but different pathways are involved at different stages of phenotypic maturation.
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PMID:Membrane mediated signaling mechanisms are used differentially by metabolites of vitamin D(3) in musculoskeletal cells. 1196 Jun 17

1. The present review focuses on the gene regulatory mechanisms involved in the control of cardiac mitochondrial energy production in the developing heart and following the onset of pathological cardiac hypertrophy. Particular emphasis has been given to the mitochondrial fatty acid oxidation (FAO) pathway and its control by members of the nuclear receptor transcription factor superfamily. 2. During perinatal cardiac development, the heart undergoes a switch in energy substrate preference from glucose in the fetal period to fatty acids following birth. This energy metabolic switch is paralleled by changes in the expression of the enzymes and protein involved in the respective pathways. 3. The postnatal activation of the mitochondrial energy production pathway involves the induced expression of nuclear genes encoding FAO enzymes, as well as other proteins important in mitochondrial energy transduction/production pathways. Recent evidence indicates that this postnatal gene regulatory effect involves the actions of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and its coactivator the PPARgamma coactivator 1 (PGC-1). 4. The PGC-1 not only activates PPARalpha to induce FAO pathway enzymes in the postnatal heart, but it also plays a pivotal role in the control of cardiac mitochondrial number and function. Thus, PGC-1 plays a master regulatory role in the high-capacity mitochondrial energy production system in the adult mammalian heart. 5. During the development of pathological forms of cardiac hypertrophy, such as that due to pressure overload, the myocardial energy substrate preference shifts back towards the fetal pattern, with a corresponding reduction in the expression of FAO enzyme genes. This metabolic shift is due to the deactivation of the PPARalpha/PGC-1 complex. 6. The deactivation of PPARalpha and PGC-1 during the development of cardiac hypertrophy involves regulation at several levels, including a reduction in the expression of these genes, as well as post-translational effects due to the mitogen-activated protein kinase pathway. Future studies aim at defining whether this transcriptional 'switch' and its effects on myocardial metabolism are adaptive or maladaptive in the hypertrophied heart.
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PMID:Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. 1198 47

The orphan nuclear receptor Nur77 (NR4A1) is a member of the nuclear receptor superfamily, which plays an important role in the regulation of LH-mediated steroidogenesis in testicular Leydig cells. The aim of the current study was to investigate the potential role of bisphenol A (BPA) on orphan nuclear receptor Nur77 gene expression and steroidogenesis. Northern blot analysis demonstrated that BPA transiently induced Nur77 mRNA expression, and protein kinase inhibitor H-89 and PD98059 strongly inhibited the induction of BPA-mediated Nur77 gene expression in mouse Leydig tumor cell line, K28. Moreover, BPA increased the activation of mitogen-activated protein kinase. Transient transfection assay demonstrated that BPA increased Nur77 gene promoter activity and Nur77 transactivation, whereas BPA did not significantly affect the interaction of Nur77 with its corepressor. Furthermore, BPA increased progesterone biosynthesis in K28 cells, which was suppressed by overexpression of dominant negative Nur77. Finally, BPA injection to prepubertal mice revealed that the expression of Nur77 mRNA was elevated, and this induction was correlated with increased concentration of testicular T in vivo. Taken together, these results demonstrated that BPA induces Nur77 gene expression and subsequently alters the steroidogenesis in testicular Leydig cells. These observations provide a novel mechanism by which BPA acts as an endocrine disrupting chemical.
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PMID:Endocrine disrupter bisphenol a induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells. 1202 Nov 84

Steroids and thyroid hormone are thought primarily to act via binding to hormone-specific nuclear receptor superfamily members. The nuclear ligand-receptor complexes then initiate transcriptional activity. Actions of steroids and iodothyronines that are nongenomic or extranuclear in mechanism have been recognized recently and new insights into such mechanisms are available. Despite their distinct structures and biologic effects, the two families of hormones have similarities in the mechanisms of their nongenomic actions. That is, both steroids and thyroid hormone appear to interact with specific cell surface G protein-coupled receptors and to activate signal transducing kinases such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Much is known about the ability of certain steroids such as estrogen and mineralocorticoids to increase [Ca2+]i acutely and stimulation of the MAPK cascade by L-T4 appears to depend upon a hormone-induced increase in [Ca2+]i via phosphoinositide pathway activation. At least in the case of iodothyronines, hormone activation of the MAPK pathway modulates the cellular activities of certain cytokines and growth factors. One of the two cell surface estrogen receptors (ERs) may be an expression of the same transcript as that for nuclear ER, whereas the mineralocorticoid and progesterone-binding proteins in the plasma membrane appear to be products of genes different from those of nuclear receptors. Iodothyronine structure-activity relationships at the plasma membrane binding site for thyroid hormone suggest that the cell surface receptor for T4 that also binds 3,5,3'-triiodo-L-T3 is different from the nuclear T3 receptor (TR). There are interfaces of nongenomic and genomic mechanisms for both steroids and thyroid hormone. For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR. Transcriptional activity of the nuclear receptor proteins can be altered by such phosphorylation.
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PMID:Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones. 1203 Jun 12

Activation of peroxisome proliferator-activated receptors (PPARs) exerts diverse effects on neoplastic cells. Recent work has shown that PPARdelta is up-regulated after loss of adenomatous polyposis coli tumor suppressor gene function and that transcriptional activation of the PPARgamma nuclear receptor can lead to inhibition of carcinoma growth. In this study, we elucidate the regulation and functional importance of PPARgamma and delta after K-Ras-transformation of intestinal epithelial cells. In conditionally K-Ras-transformed rat intestinal epithelial cells (IEC-iK-Ras), the level and activity of PPARdelta were markedly increased. PPARdelta up-regulation occurred due to increased mitogen-activated protein kinase activity and receptor activation required the endogenous production of prostacyclin via the cyclooxygenase-2 pathway. We also demonstrate that activation of the PPARgamma nuclear receptor has antineoplastic effects in Ras-transformed cells. Activation of PPARgamma resulted in a delay in transit through the G(1) phase of the cell cycle that was associated with inhibition of phosphatidylinositol 3'-kinase/Akt activity and a reduction of cyclin D1 expression. Therefore, these two PPAR nuclear receptors, which are structurally related, have distinct roles during neoplastic transformation. PPARgamma appears to modulate differentiation and signal growth inhibition, whereas PPARdelta is up-regulated by oncogenic Ras and activated by cyclooxygenase-2-derived prostaglandins.
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PMID:Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells. 1203 46


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