Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-gamma is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-gamma, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor. Here we show that ligand binding by PPAR-gamma is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-gamma. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-gamma and that are likely to extend to other members of the nuclear-receptor superfamily.
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PMID:Interdomain communication regulating ligand binding by PPAR-gamma. 984 75

The peroxisome proliferator-activated receptor-gamma (PPARgamma) transcription factor plays a pivotal role in adipocyte differentiation and metabolic regulation. The transcriptional activity of PPARgamma is positively modulated by ligand binding and negatively regulated by phosphorylation mediated by the MEK/ERK signaling pathway. The phosphorylation of mouse PPARgamma1 at Ser82 by ERK causes a decrease in both basal and ligand-dependent transcriptional activity. In this report we examined the ability of other mitogen-activated protein kinase family members to phosphorylate PPARgamma1. We demonstrate that in vitro, PPARgamma1 is efficiently phosphorylated by JNK/SAPK (c-Jun N-terminal kinase or stress-activated protein kinase) but only weakly phosphorylated by p38. In transfected 293T cells, PPARgamma1 is phosphorylated at Ser82 in response to known JNK activators such as UV irradiation and anisomycin treatment. This phosphorylation is not blocked by either the specific MEK inhibitor PD98059 or the p38 inhibitor SB203580, indicating that it is independent of the MEK/ERK and p38 signaling pathways. Finally, in transient transfection reporter assays, activation of JNK by anisomycin or by overexpression of MKK4 (the upstream JNK kinase) decreased ligand-dependent PPARgamma1 transcriptional activity. These results suggest that the activation of the JNK/SAPK pathway by extracellular signals, perhaps by inflammatory cytokines such as tumor necrosis factor-alpha, would result in a reduction of PPARgamma transcriptional activity and reduce the effects of PPARgamma ligands.
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PMID:c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-gamma1 and negatively regulates its transcriptional activity. 988 50

Hepatic peroxisome proliferation induced by structurally diverse non-genotoxic carcinogens is mediated by the nuclear receptor peroxisome proliferator-activated receptor (PPARalpha) and can be inhibited by growth hormone (GH). GH-stimulated Janus kinase-signal transducer and activator of transcription 5b (JAK2/STAT5b) signaling and the PPAR activation pathway were reconstituted in COS-1 cells to investigate the mechanism for this GH inhibitory effect. Activation of STAT5b signaling by either GH or prolactin inhibited, by up to 80-85%, ligand-induced, PPARalpha-dependent reporter gene transcription. GH failed to inhibit 15-deoxy-Delta12, 14-prostaglandin-J2-stimulated gene transcription mediated by an endogenous COS-1 PPAR-related receptor. GH inhibition of PPARalpha activity required GH receptor and STAT5b and was not observed using GH-activated STAT1 in place of STAT5b. GH inhibition was not blocked by the mitogen-activated protein kinase pathway inhibitor PD98059. STAT5b-PPARalpha protein-protein interactions could not be detected by anti-STAT5b supershift analysis of PPARalpha-DNA complexes. The GH inhibitory effect required the tyrosine phosphorylation site (Tyr-699) of STAT5b, an intact STAT5b DNA binding domain, and the presence of a COOH-terminal trans-activation domain. Moreover, GH inhibition was reversed by a COOH-terminal-truncated, dominant-negative STAT5b mutant. STAT5b must thus be nuclear and transcriptionally active to mediate GH inhibition of PPARalpha activity, suggesting an indirect inhibition mechanism, such as competition for an essential PPARalpha coactivator or STAT5b-dependent synthesis of a more proximal PPARalpha inhibitor. The cross-talk between STAT5b and PPARalpha signaling pathways established by these findings provides new insight into the mechanisms of hormonal and cytokine regulation of hepatic peroxisome proliferation.
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PMID:Cross-talk between janus kinase-signal transducer and activator of transcription (JAK-STAT) and peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling pathways. Growth hormone inhibition of pparalpha transcriptional activity mediated by stat5b. 991 97

Extracellular factors and intracellular signaling pathways involved in early events of adipocyte differentiation are poorly defined. It is shown herein that expression of leukemia inhibitory factor (LIF) and LIF receptor is developmentally regulated during adipocyte differentiation. Preadipocytes secrete bioactive LIF, and an antagonist of LIF receptor inhibits adipogenesis. Genetically modified embryonic stem (ES) cells combined with culture conditions to commit stem cells into the adipocyte lineage were used to examine the requirement of LIF receptor during in vitro development of adipose cells. The capacity of embryoid bodies derived from lifr(-/-) ES cells to undergo adipocyte differentiation is dramatically reduced. LIF addition stimulates adipocyte differentiation of Ob1771 and 3T3-F442A preadipocytes and that of peroxisome proliferator-activated receptor gamma2 ligand-treated mouse embryonic fibroblasts. Expression of the early adipogenic transcription factors C/EBPbeta and C/EBPdelta is rapidly stimulated following exposure of preadipose cells to LIF. The selective inhibitors of mitogen-activated protein kinase kinase, i.e. PD98059 and U0126, inhibit LIF-induced C/EBP gene expression and prevent adipocyte differentiation induced by LIF. These results are in favor of a model that implicates stimulation of LIF receptor in the commitment of preadipocytes to undergo terminal differentiation by controlling the early expression of C/EBPbeta and C/EBPdelta genes via the mitogen-activated protein kinase cascade.
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PMID:Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade. 1045 74

In osteoporosis, the bone marrow stroma osteogenic cell population declines and adipocyte numbers increase. We recently showed that oxidized lipids inhibit differentiation of preosteoblasts. In this report, we assess the effect of minimally oxidized low density lipoprotein (MM-LDL) on osteoblastic differentiation of murine marrow stromal cells, M2-10B4. MM-LDL, but not native LDL, inhibited stromal cell osteoblastic differentiation as demonstrated by inhibition of alkaline phosphatase activity, collagen I processing, and mineralization, through a mitogen-activated protein kinase-dependent pathway. In addition, marrow stromal cells from C57BL/6 mice fed a high fat, atherogenic diet failed to undergo osteogenic differentiation in vitro. The ability of MM-LDL to regulate adipogenesis was also assessed. Treatment of M2-10B4 as well as 3T3-L1 preadipocytes with MM-LDL, but not native LDL, promoted adipogenic differentiation in the presence of peroxisome proliferator-activated receptor (PPAR) gamma agonist thiazolidinediones, BRL49653 and ciglitizone. Based on promoter-reporter construct experiments, MM-LDL may be acting in part through activating PPARalpha. These observations suggest that LDL oxidation products promote osteoporotic loss of bone by directing progenitor marrow stromal cells to undergo adipogenic instead of osteogenic differentiation. These data lend support to the "lipid hypothesis of osteoporosis."
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PMID:Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells. 1062 66

CD36, the macrophage type B scavenger receptor, binds and internalizes oxidized low density lipoprotein, a key event in the development of macrophage foam cells within atherosclerotic lesions. Expression of CD36 in monocyte/macrophages is dependent on differentiation status and exposure to soluble mediators. In this study, we investigated the effect of transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 on the expression of CD36 in macrophages. Treatment of phorbol ester-differentiated THP-1 macrophages with TGF-beta1 or TGF-beta2 significantly decreased expression of CD36 mRNA and surface protein. TGF-beta1/TGF-beta2 also inhibited CD36 mRNA expression induced by oxidized low density lipoprotein and 15-deoxyDelta(12,14) prostaglandin J(2), a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, suggesting that the TGF-beta1/TGF-beta2 down-regulated CD36 expression by inactivating PPAR-gamma-mediated signaling. TGF-beta1/TGF-beta2 increased phosphorylation of both mitogen-activated protein (MAP) kinase and PPAR-gamma, whereas MAP kinase inhibitors reversed suppression of CD36 and inhibited PPAR-gamma phosphorylation induced by TGF-beta1/TGF-beta2. Finally, MAP kinase inhibitors alone increased expression of CD36 mRNA and surface protein but had no effect on PPAR-gamma protein levels. Our data demonstrate for the first time that TGF-beta1 and TGF-beta2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPAR-gamma, and a decrease in CD36 gene transcription by phosphorylated PPAR-gamma.
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PMID:Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. 1062 69

Adult human mesenchymal stem cells are primary, multipotent cells capable of differentiating to osteocytic, chondrocytic, and adipocytic lineages when stimulated under appropriate conditions. To characterize the molecular mechanisms that regulate osteogenic differentiation, we examined the contribution of mitogen-activated protein kinase family members, ERK, JNK, and p38. Treatment of these stem cells with osteogenic supplements resulted in a sustained phase of ERK activation from day 7 to day 11 that coincided with differentiation, before decreasing to basal levels. Activation of JNK occurred much later (day 13 to day 17) in the osteogenic differentiation process. This JNK activation was associated with extracellular matrix synthesis and increased calcium deposition, the two hallmarks of bone formation. Inhibition of ERK activation by PD98059, a specific inhibitor of the ERK signaling pathway, blocked the osteogenic differentiation in a dose-dependent manner, as did transfection with a dominant negative form of MAP kinase kinase (MEK-1). Significantly, the blockage of osteogenic differentiation resulted in the adipogenic differentiation of the stem cells and the expression of adipose-specific mRNAs peroxisome proliferator-activated receptor gamma2, aP2, and lipoprotein lipase. These observations provide a potential mechanism involving MAP kinase activation in osteogenic differentiation of adult stem cells and suggest that commitment of hMSCs into osteogenic or adipogenic lineages is governed by activation or inhibition of ERK, respectively.
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PMID:Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. 1073 16

In human coronary artery vascular smooth muscle (hcaVSM) cells, the mechanisms that mediate the antiproliferative effects of ligands for the peroxisome proliferator-activated receptor-gamma (PPAR gamma) and the retinoid X receptor-alpha (RXR alpha) are unclear. Dimerization of PPAR gamma with RXR alpha and occupancy by both ligands is required for maximal activation. Accordingly, we determined whether the antiproliferative activity of the PPAR gamma ligands, troglitazone or 15-deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2), was enhanced with the RXR alpha ligand, 9-cis-retinoic acid (9-cis-RA). Incubation of actively proliferating hcaVSM cells with either troglitazone or 15d-PGJ2 resulted in a dose-dependent inhibition of proliferation with half-maximal inhibitory concentrations (IC(50)s) of 13 and 2 microM, respectively. Quiescent cells incubated with troglitazone or 15d-PGJ2 and subsequently stimulated with PDGF-BB showed a concentration-dependent decrease in the active form of MAP kinase, suggesting that inhibition of cell growth by troglitazone may involve the MAP kinase pathway, an important growth activation pathway in VSM cells. Incubation of cells with either 0.1 or 1.0 microM 9-cis-RA inhibited cell growth to a similar degree. Addition of troglitazone or 15d-PGJ2 to cells in combination with either concentration of 9-cis-RA resulted in a striking increase in growth inhibition, and was accompanied by an approximately 4-fold reduction in the IC(50)s for both PPAR gamma ligands. These findings imply that RXR alpha activation by 9-cis-RA synergistically enhanced inhibition of hcaVSM cell growth. The precise nature of this cooperative interaction between PPAR gamma and RXR alpha remains to be determined.
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PMID:Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor-alpha exert synergistic antiproliferative effects on human coronary artery smooth muscle cells. 1086 Aug 64

We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth. alpha(1)-adrenergic agonist-induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator-activated receptor-alpha (PPARalpha) response element. Ventricular pressure overload studies in mice, together with PPARalpha overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPARalpha gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPARalpha is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.
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PMID:Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. 1086 87

Angiotensin II (Ang II) stimulates the activation of extracellular signal-regulated kinase (ERK), a subgroup of the mitogen-activated protein kinase (MAPK) family, in cultured vascular smooth muscle cells (VSMC). This ERK activation was recently shown to be a critical regulatory factor for Ang II-mediated migration and growth. It has been demonstrated that the thiazolidinedione troglitazone (TRO) blocked Ang II-induced DNA synthesis and migration in VSMC. Here we provide evidence for TRO to inhibit Ang II-induced ERK activation which was suggested to constitute the mechanism by which this agent blocks Ang II-induced VSMC growth and migration. We have found that pretreatment with PD98059, which selectively blocks the activity of ERK pathway at the level of MAPK kinase, decreased Ang II-induced AP-1 activation and that TRO is capable of inhibiting Ang II-induced AP-1 activation. On the other hand, the other thiazolidinediones pioglitazone (PIO) and rosiglitazone (ROSI) had little effect on Ang II-induced activation of ERK or AP-1, suggesting the inhibitory effects of TRO on VSMC activation by Ang II be independent of the peroxisome proliferator-activated receptor-gamma (PPARgamma) for which thiazolidinediones are ligands. Ang II-induced ERK activation was inhibited by protein kinase C (PKC)-specific inhibitor GF109203X, while TRO was also able to block PKC activator phorbol 12 myristate 13-acetate (PMA)-induced ERK activation. Accordingly, TRO may inhibit Ang II-induced MAPK activation at least partly by an inhibition of PKC. These results support the assumption that by targeting MAPK activation, TRO may inhibits the critical signaling steps leading to restenosis and atherosclerosis that may result in part from dysregulated VSMC growth and migration induced by Ang II.
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PMID:The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II. 1089 86


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