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)

Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor of a variety of epithelial cell types. The primary signaling mechanism involved in mediating this and other cellular effects of TGF-beta is still unknown. We report here that both TGF-beta 1 and TGF-beta 2 resulted in a rapid activation of mitogen-activated protein kinase (MAPK) p44mapk, occurring within 5-10 min of growth factor addition. This effect occurred in exponentially proliferating cultures of intestinal epithelial (IEC) 4-1 cells under conditions in which DNA synthesis was inhibited by 95% to 98%. Furthermore, TGF-beta 2 induced a sustained activation of p44mapk under these conditions, lasting for at least 90 min after initial growth factor treatment. Another TGF-beta-sensitive epithelial cell line (CCL 64) displayed a similar rapid increase in p44mapk activity when treated with TGF-beta 1. In contrast, in IEC 4-6 cells that are resistant to TGF-beta effects on growth and DNA synthesis, TGF-beta 2 treatment did not result in an activation of p44mapk. In contrast to the results in proliferating cultures, treatment of quiescent cultures of IEC 4-1 cells with TGF-beta 2 resulted in no significant change in either DNA synthesis or p44mapk activity within 15 min of TGF-beta addition. In contrast, addition of the growth-stimulatory combination of factors (epidermal growth factor + insulin + transferrin = EIT) to quiescent and proliferating IEC 4-1 cells stimulated DNA synthesis and resulted in a sustained activation of p44mapk. Together, our results suggest an association between activation of p44mapk and both TGF-beta-mediated growth inhibition and EIT-mediated growth stimulation. This suggests that the specificity for the cellular effects of growth factors may not occur at the level of MAPK activation per se, but rather at downstream events that include phosphorylation of distinct transcriptional complexes and activation of a select assortment of genes. With regard to TGF-beta specifically, we have proposed a model to explain how activation of p44mapk may be associated with a growth-inhibitory response.
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PMID:Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. 770 48

Cell proliferation requires the co-ordinate triggering of several protein kinases of Ser/Thr specificity such as p70 S6 kinase (S6K), which phosphorylates the ribosomal S6 protein and thus increases translation of mRNAs with polypyrimidine tracts. The multiplicity of signaling pathways leading to p70 S6K activation are not fully elucidated. However, several reports have indicated that the activation of p70 S6K is independent of mitogen-activated protein kinase (MAPK) activation. Interestingly, we and others have shown that constitutive activation of the MAPK pathway promotes cell proliferation, suggesting that this cascade is able to activate p70 S6K, a key step to trigger cell cycle entry. In this report we demonstrate that transfection of constitutively active mitogen-activated protein kinase kinase 1 in CCL 39 cells leads to activation of p70 S6K. Furthermore, we have established a cell line that stably expresses DeltaRaf-1:ER, an estradiol-regulated form of oncogenic Raf-1. The addition of estradiol to these cells was sufficient to elicit rapid activation of mitogen-activated protein kinase kinase 1, MAPK, and p70 S6K. Surprisingly, the activation of p70 S6K is not mediated by MAPK because blocking MAPK activation by expression of the phosphatase MKP-1 did not prevent p70 S6K activation by DeltaRaf-1:ER. In conclusion, we have demonstrated that activation of p70 S6K by DeltaRaf-1:ER is mediated by a new MAPK-independent pathway. This pathway is resistant to low nanomolar concentrations of wortmannin, indicating that it does not involve membrane-bound phosphatidylinositol-trisphosphate kinase activation.
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PMID:Oncogenic Raf-1 activates p70 S6 kinase via a mitogen-activated protein kinase-independent pathway. 866 20

With the aim of interrupting the growth factor-stimulated Ras signaling pathway at the level of the Grb2-Sos interaction, a peptidimer, made of two identical proline-rich sequences from Sos linked by a lysine spacer, was designed using structural data from Grb2 and a proline-rich peptide complexed with its SH3 domains. The peptidimer affinity for Grb2 is 40 nM whereas that of the monomer is 16 microM, supporting the dual recognition of both Grb2 SH3 domains by the dimer. At 50 nM, the peptidimer blocks selectively Grb2-Sos complexation in ER 22 (CCL 39 fibroblasts overexpressing epidermal growth factor receptor) cellular extracts. The peptidimer specifically recognizes Grb2 and does not interact with PI3K or Nck, two SH3 domain-containing adaptors. The peptidimer was modified to enter cells by coupling to a fragment of Antennapedia homeodomain. At 10 microM, the conjugate inhibits the Grb2-Sos interaction (100%) and MAP kinase (ERK1 and ERK2) phosphorylation (60%) without modifying cellular growth of ER 22 cells. At the same concentration, the conjugate also inhibits both MAP kinase activation induced by nerve growth factor or epidermal growth factor in PC12 cells, and differentiation triggered by nerve growth factor. Finally, when tested for its antiproliferative activity, the conjugate was an efficient inhibitor of the colony formation of transformed NIH3T3/HER2 cells grown in soft agar, with an IC50 of around 1 microM. Thus, the designed peptidimers appear to be interesting leads to investigate signaling and intracellular processes and for designing selective inhibitors of tumorigenic Ras-dependent processes.
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PMID:A Sos-derived peptidimer blocks the Ras signaling pathway by binding both Grb2 SH3 domains and displays antiproliferative activity. 987 27

Our previous studies have shown that, through an active transport process, serotonin (5-HT) rapidly elevates O(-)(2). formation, stimulates protein phosphorylation, and enhances proliferation of bovine pulmonary artery smooth muscle cells (SMCs). We presently show that 1 microM 5-HT also rapidly elevates phosphorylation and activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) 1 and ERK2 of SMCs, and the enhanced phosphorylation is blocked by the antioxidants Tiron, N-acetyl-L-cysteine (NAC), and Ginkgo biloba extract. Inhibition of MAP kinase with PD-98059 failed to block enhanced O(-)(2). formation by 5-HT. Chinese hamster lung fibroblasts (CCL-39 cells), which demonstrate both 5-HT transporter and receptor activity, showed a similar response to 5-HT (i.e., enhanced mitogenesis, O(-)(2). formation, and ERK1 and ERK2 phosphorylation and activation). Unlike SMCs, they also responded to 5-HT receptor agonists. We conclude that downstream signaling of MAP kinase is a generalized cellular response to 5-HT that occurs secondary to O(-)(2). formation and may be initiated by either the 5-HT transporter or receptor depending on the cell type.
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PMID:Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion. 1044 22

We have demonstrated that pancreatitis-associated ascitic fluid contributes to hepatocyte injury during acute pancreatitis; a phenomenon independent of ascites' enzymatic content and Kupffer cell-derived cytokines. Our aim is to characterize the mechanisms of pancreatitis-associated ascitic fluid induced hepatocyte death. NIH mice were injected intraperitoneally with pathogen-free pancreatitis-associated ascitic fluid. Twenty-four hours later, serum AST, ALT, LDH, and hepatocyte apoptosis (TUNEL) were measured. Human hepatocytes (CCL-13) were treated with pancreatitis-associated ascitic fluid +/-SB203580 or caspase-3 inhibitor-II. Mitochondrial membrane integrity was determined by DiOC6 staining. Apoptosis was measured by TUNEL staining and flow cytometry after dual labeling with Annexin-V/7-AAD. Data are mean +/- SEM of triplicates. Pancreatitis-associated ascitic fluid increased serum AST, ALT, LDH, and apoptotic cells in the mouse liver (all P < 0.03 vs. sham). In CCL-13 cells, pancreatitis-associated ascitic fluid induced a time and dose-dependent increase in apoptosis, in addition to p38-MAPK phosphorylation (P = 0.02 vs. control), caspase-3 cleavage (P < 0.03 vs. control) and decreased DiOC6 mitochondrial staining (P < 0.01 vs. control). Both caspase-3 inhibitor-II and SB203580 decreased apoptosis, but the former had no effect on DiOC6 staining. Pancreatitis-associated ascitic fluid induces liver injury and hepatocyte apoptosis by activating p38-MAPK and caspase-3 dependent pro-apoptotic pathways.
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PMID:Liver injury during acute pancreatitis: the role of pancreatitis-associated ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis. 1260 Apr 44

Combination studies of celecoxib and chemotherapeutic agents suggest that combining cyclooxygenase-2 inhibitors with other agents may have supra-additive or synergistic effects on tumor growth inhibition. Carboxyamido-triazole (CAI), a voltage-independent calcium channel inhibitor, has been shown to induce growth inhibition and apoptosis in cancer cells. We found that continuous exposure to cytostatic doses of CAI and LM-1685, a celecoxib analogue, reduced the proliferation and survival of seven human cancer cell lines by at least one log (P < or = 0.001) over either agent alone. To explore the mechanism of action of this combination, we further studied the effects of LM-1685/CAI on CCL-250 colorectal carcinoma cells. We found that the supra-additive antiproliferative effects occurred throughout a range of LM-1685 doses (5-25 micromol/L) and paralleled a decrease in COX-2 activity as measured by prostaglandin E2 production. In these cells, treatment with LM-1685/CAI suppressed the extracellular signal-regulated kinase pathway within the first hour but ultimately results in high, sustained activation of ERK over a 9-day period (P = 0.0005). Suppression of cyclin D1 and phospho-AKT, and cleavage of caspase-3 and PARP were concomitant with persistent ERK activation. Addition of PD98059, a MEK-1 inhibitor, suppressed ERK activation and significantly but incompletely reversed these signaling events and apoptosis. Flow cytometry experiments revealed that the CAI/LM-1685 combination induced a 3-fold increase in apoptosis over control (P = 0.005) in 3 days. We show that the combination of CAI and LM-1685 produces a cytotoxic effect by suppressing proliferation and triggering apoptosis.
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PMID:Supra-additive growth inhibition by a celecoxib analogue and carboxyamido-triazole is primarily mediated through apoptosis. 1586 84

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. PPAR-gamma ligands have been demonstrated to inhibit growth of several cancer cells. In this study, two human lung cancer cells (NCI-H23 and CRL-2066) and one human lung normal cell (CRL-202) were used for the experiments. The results showed that in consistence with the loss of viability, troglitazone (TGZ) induced apoptosis of CRL-2066 and NCI-H23 cells but not CCL-202 cells. TGZ upregulated PPAR-gamma expression in all the three lung cell lines, especially in the cancer cells. In association of the time-dependent inhibition of the cell proliferation, TGZ downregulated the expression of Bcl-w and Bcl-2 but activated extracellular signal-regulated kinase (ERK)1/2 and p38, suggesting that the growth-inhibitory effect of TGZ is associated with the reduction of Bcl-w and Bcl-2 and the increase of ERK1/2 and p38 activation. SAPK/JNK activation assay showed a decreased activity in all the three cell lines tested after TGZ treatment. It was also demonstrated that TGZ could activate PPAR-gamma transcriptionally. We conclude that TGZ inhibits growth of human lung cancer cells via the induction of apoptosis and the inhibition of cell growth, at least in part, in a PPAR-gamma-relevant manner. The mechanism of TGZ is associated with the activation of ERK and p38, the reduction of SAPK/JNK activity, and the alteration of Bcl-w and Bcl-2.
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PMID:Activation of peroxisome proliferator-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth. 1614 72

IL-13 dysregulation plays a critical role in the pathogenesis of a variety of inflammatory and remodeling diseases. In these settings, STAT6 is believed to be the canonical signaling molecule mediating the tissue effects of IL-13. Signaling cascades involving MAPKs have been linked to inflammation and remodeling. We hypothesized that MAPKs play critical roles in effector responses induced by IL-13 in the lung. We found that Tg IL-13 expression in the lung led to potent activation of ERK1/2 but not JNK1/2 or p38. ERK1/2 activation also occurred in mice with null mutations of STAT6. Systemic administration of the MAPK/ERK kinase 1 (MEK1) inhibitor PD98059 or use of Tg mice in which a dominant-negative MEK1 construct was expressed inhibited IL-13-induced inflammation and alveolar remodeling. There were associated decreases in IL-13-induced chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL-1, RANTES/CCL-5), MMP-2, -9, -12, and -14, and cathepsin B and increased levels of alpha1-antitrypsin. IL-13-induced tissue and molecular responses were noted that were equally and differentially dependent on ERK1/2 and STAT6 signaling. Thus, ERK1/2 is activated by IL-13 in the lung in a STAT6-independent manner where it contributes to IL-13-induced inflammation and remodeling and is required for optimal IL-13 stimulation of specific chemokines and proteases as well as the inhibition of specific antiproteases. ERK1/2 regulators may be useful in the treatment of IL-13-induced diseases and disorders.
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PMID:ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo. 1637 21

Evidence from the animal model suggests that proteasome inhibitors may have immunosuppressive properties; however, their effects on the human immune system remain poorly investigated. Here, we show that bortezomib, a proteasome inhibitor with anticancer activity, impairs several immune properties of human monocyte-derived dendritic cells (DCs). Namely, exposure of DCs to bortezomib reduces their phagocytic capacity, as shown by FITC-labeled dextran internalization and mannose-receptor CD206 down-regulation. DCs treated with bortezomib show skewed phenotypic maturation in response to stimuli of bacterial (lipopolysaccharide [LPS]) and endogenous sources (including TNF-alpha and CD40L), as well as reduced cytokine production and immunostimulatory capacity. LPS-induced CCL-2/MCP-1 and CCL5/RANTES secretions by DCs were prevented by DC treatment with bortezomib. Finally, CCR7 up-regulation in DCs exposed to LPS as well as migration toward CCL19/MIP-3beta were strongly impaired. As a suitable mechanism for these effects, bortezomib was found to down-regulate MyD88, an essential adaptor for TLR signaling, and to relieve LPS-induced activation of NF-kappaB, IRF-3, and IRF-8 and of the MAP kinase pathway. In summary, inhibition of DC function may represent a novel mechanism by which proteasome inhibitors exert immunomodulatory effects. These compounds could prove useful for tuning TLR signaling and for the treatment of inflammatory and immune-mediated disorders.
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PMID:Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. 1653 13

Tuberculosis (TB) of the CNS (CNS-TB) carries a high mortality. Disease pathology is characterized by widespread destruction of CNS tissues. Matrix metalloproteinase-9 (MMP-9) is able to catabolyze specific components of the CNS tissue matrix and blood-brain barrier. Increased cerebrospinal fluid MMP-9 concentrations are associated with tissue damage, leukocyte infiltration, and death in CNS-TB. Using zymography, Western analysis, and transcription factor assays, we investigated mechanisms regulating MMP-9 activity in CNS-TB. We demonstrate that conditioned media from monocytes infected with Mycobacterium tuberculosis (CoMTB) induce MMP-9 secretion from astrocytes (U373-MG). IL-1beta and TNF-alpha are necessary but not sufficient for such induction of astrocyte MMP-9 secretion. CoMTB up-regulates AP-1 DNA-binding activity, and the c-Jun, FosB, and JunB subunits are particularly increased. MMP-9 secretion from CoMTB-stimulated astrocytes is dependent on the activity of p38, Erk, and Jnk MAPKs. Phosphorylation of p38, Erk, and Jnk is activated rapidly, peaking 30 min poststimulation with CoMTB. Inhibition of IL-1beta but not TNF-alpha in CoMTB decreases p38, Erk, and Jnk activity in astrocytes. Consistently, IL-1beta signals through the MAPK cascade at physiological levels, whereas TNF-alpha, IL-6, IL-10, CCL-2, CCL-5, and CXCL-8 (all present in CoMTB) do not. In summary, the data suggest that monocyte-dependent cytokine networks may play a key role in the development of a matrix-degrading environment during CNS-TB.
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PMID:Monocytes infected with Mycobacterium tuberculosis regulate MAP kinase-dependent astrocyte MMP-9 secretion. 1707 49


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