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)

Environmental signals, such as nutrient availability and physiological stresses, modulate the cell cycle and cell size of the fission yeast Schizosaccharomyces pombe. However, little is known about how these signals are transmitted to the central cell cycle regulator, Cdc2, the cyclin-dependent kinase that induces mitosis. We show here genetic evidence that medium alkalization stimulates mitosis and consequently reduces cell size, either through the Nim1-Wee1 cascade, which regulates the inhibitory phosphorylation of Cdc2 at Tyr(15), or through the Cdc2-activating phosphatase, Cdc25. Alkaline stress stimulates phosphorylation of Nim1, accumulation of Cdc25 and dephosphorylation of Cdc2 at Tyr(15). We also show that osmostress stimulates mitosis through two independent pathways: one stimulates accumulation of Cdc25, and another dephosphorylation of Cdc2 at Tyr(15). However, our analysis demonstrates that these environmental stresses can stimulate mitosis independently of dephosphorylation of Cdc2 at Tyr(15). The S. pombe MAP kinase, Spc1, was required for the steady-state level of Cdc25 in the normal cell cycle and for its accumulation in response to alkaline stress and nutritional starvation.
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PMID:Multiple pathways regulating fission yeast mitosis upon environmental stresses. 1080 22

Mitogen-activated protein (MAP) kinases, p42(MAPK) and p44(MAPK), are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G(1)/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G(1) phase, once the known mechanisms by which MAP kinase controls G(1) progression, accumulation of G(1) cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control.
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PMID:Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase. 1090 50

This study was designed to elucidate the mechanism underlying the inhibition of endothelial cell growth by laminar shear stress. Tumor suppressor gene p53 was increased in bovine aortic endothelial cells subjected to 24 h of laminar shear stress at 3 dynes (1 dyne = 10 microN)/cm(2) or higher, but not at 1.5 dynes/cm(2). One of the mechanisms of the shear-induced increase in p53 is its stabilization after phosphorylation by c-Jun N-terminal kinase. To investigate the consequence of the shear-induced p53 response, we found that prolonged laminar shear stress caused increases of the growth arrest proteins GADD45 (growth arrest and DNA damage inducible protein 45) and p21(cip1), as well as a decrease in phosphorylation of the retinoblastoma gene product. Our results suggest that prolonged laminar shear stress causes a sustained p53 activation, which induces the up-regulation of GADD45 and p21(cip1). The resulting inhibition of cyclin-dependent kinase and hypophosphorylation of retinoblastoma protein lead to endothelial cell cycle arrest. This inhibition of endothelial cell proliferation by laminar shear stress may serve an important homeostatic function by preventing atherogenesis in the straight part of the arterial tree that is constantly subjected to high levels of laminar shearing.
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PMID:Molecular mechanism of endothelial growth arrest by laminar shear stress. 1092 Feb 9

There is an increasing interest in identifying potent cancer preventive and therapeutic agents against prostate cancer (PCA). In a recent study, we showed that a polyphenolic fraction isolated from grape seeds (hereafter referred to as GSP) that is substantially rich in antioxidant procyanidins exerts exceptionally high preventive effects against tumorigenesis in a murine skin model. In the present study, we investigated the anticarcinogenic effect of GSP against PCA by employing DU145 human prostate carcinoma cells. GSP treatment (10-100 microg/mL doses for 2-6 d) of cells resulted in a highly significant (P < 0.01-0.001) inhibition of cell growth in both dose- and time-dependent manner. Compared with the vehicle, 2 d of GSP treatment resulted in 27, 39, and 76% growth inhibition at 50, 75, and 100 microg/mL doses, respectively, whereas 28-97% and 12-98% inhibition was evident at 10-100 microg/mL doses of GSP after 4 and 6 d of treatment, respectively. These doses of GSP also resulted in dose- and time-dependent cell death (6-50%, P <0.1-0. 001) that was later characterized as apoptotic death. In molecular mechanistic studies, treatment of DU145 cells with GSP at 25-75 microg/mL doses for 24, 48, and 72 h resulted in 77-88%, 65-93%, and 38-98% reduction, respectively (P < 0.001), in phospho-extracellular signal-regulated protein kinase (ERK) 1 and 78%, 19-76%, and 63-71% reduction (P < 0.1-0.001) in phospho-ERK2 levels, respectively. In other studies, similar doses of GSP showed up to 1.9-fold increases in Cip1/p21 and a significant (P < 0.001) decrease in cyclin-dependent kinase (CDK) 4 (up to 90% decrease), CDK2 (up to 50% decrease), and cyclin E (up to 60% decrease). GSP treatment of DU145 cells also resulted in a significant (P < 0.001) G1 arrest in cell-cycle progression in a dose-dependent manner. The growth-inhibitory and cell-death effects of GSP were also observed in another human PCA line, LNCaP. Together, these results suggest that GSP may exert strong anticarcinogenic effect against PCA and that this effect possibly involves modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest, cell-growth inhibition, and apoptotic death. Mol. Carcinog. 28:129-138, 2000.
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PMID:Anticarcinogenic effect of a polyphenolic fraction isolated from grape seeds in human prostate carcinoma DU145 cells: modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest and apoptosis. 1094 29

Prostate cancer (PCA) is the most common invasive malignancy and leading cause (after lung) of cancer deaths in males. Since PCA is initially androgen-dependent, strategies are targeted toward androgen depletion for its control. However, tumor re-growth mostly occurs following this modality, and is androgen-independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and associated ligands have been shown to be the causal genetic events in PCA progression. These genetic alterations lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptor (e.g. epidermal growth factor receptor [erbB1] and associated ligand (e.g. transforming growth factor-alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we rationalized that inhibiting these epigenetic events would be useful in controlling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavones are being studied extensively as cancer-preventive and interventive agents. Therefore, we focused our attention on silymarin, genistein, and epigallocatechin 3-gallate (EGCG), present in milk thistle, soy beans, and green tea, respectively. The effect of these agents was assessed on the erbB1-Shc-ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and cell growth and death. In androgen-independent human prostate carcinoma DU145 cells, silymarin, genistein, and EGCG resulted in a significant to complete inhibition of transforming growth factor-alpha-caused activation of membrane receptor erbB1 followed by inhibition of downstream cytoplasmic signaling target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also inhibited ERK1/2 activation, suggesting that these agents impair the activation of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a further increase in ERK1/2 activation was observed that was related to its pro-oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resulted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein also showed cell death. A more profound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Together, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer.
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PMID:Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. 1100 41

Constitutive activation of the ERK pathway is associated with the neoplastic phenotype of a relatively large number of human tumor cells. Blockade of the ERK pathway by treatment with PD98059, a specific inhibitor of mitogen-activated protein (MAP) kinase/ERK kinase (MEK), completely suppressed the growth of tumor cells in which the pathway is constitutively activated (RPMI-SE and HT1080 cells). Consistent with its prominent antiproliferative effect, PD98059 induced a remarkable G(1) cell cycle arrest, followed by a modest apoptotic response, in these tumor cells. Selective up-regulation of p27(Kip1) was observed after PD98059 treatment of RPMI-SE and HT1080 cells. Overexpression in RPMI-SE cells of either a kinase-negative form of MEK1 or wild-type MAP kinase phosphatase-3 also induced up-regulation of p27(Kip1). The up-regulation of p27(Kip1) correlated with increased association of p27(Kip1) with cyclin E-cyclin-dependent kinase (CDK) 2 complexes, a concomitant inhibition of cyclin E-CDK2 kinase activity, and a consequent decrease in the phosphorylation state of retinoblastoma protein, which would culminate in the marked G(1) cell cycle arrest observed in these tumor cells. These results suggest that the complete growth suppression that follows specific blockade of the ERK pathway in tumor cells in which the pathway is constitutively activated is mediated by up-regulation of p27(Kip1).
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PMID:Blockade of the extracellular signal-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively activated: up-regulation of p27(Kip1). 1103 Dec 57

In a previous study, we prepared short-chain fatty acid (SCFA) mixtures mimicking the composition of the digested fibers from wheat bran, oat bran, pectin, and cellulose and tested the products on U4 cells, a cell-line model for normal colonocytes. These SCFA mixes induced the cyclin-dependent kinase (cdk) inhibitors p21 and p27, which bound to cdk2/cyclin E and cdk4/cyclin D1 complexes, blocking their kinase activity and arresting cell growth. SCFAs from digested fiber may control intestinal crypt height in vivo by inducing apoptosis in growth-arrested cells at the top of the crypt. In the present study, we report that SCFA mixes induced apoptosis of U4 cells and unexpectedly caused both a sustained activation of the stress-activated protein kinase c-jun N-terminal kinase 1 (JNK1) and downregulation of the tumor suppressor protein p53. JNK1 bound to p53, and the amount of JNK1-bound p53 accurately reflected the amount of total cellular p53. After activation by SCFAs, JNK1 phosphorylated its bound p53. This phosphorylation is likely to have converted p53 into an apoptotic target because p53 breakdown correlated with caspase-3 activity, was inhibited by a caspase-3 inhibitor in a dose-dependent manner, and was inhibited by transfection of dominant-negative JNK1. Because JNK1 activation was sustained in SCFA-treated U4 cells, JNK1 can bind, phosphorylate, and release p53 for proteolysis and then continue this cycle until many p53 molecules have been phosphorylated. Loss of p53 protein was likely due to proteolysis and not to transcriptional changes because a sixfold decrease in p53 protein occurred within 3-24 h of SCFA treatment, whereas p53 mRNA levels were downregulated as much only after 2-3 d. SCFA mixes targeted p53 and possibly other cellular proteins for degradation during apoptosis by causing a sustained activation of JNKs.
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PMID:Downregulation of p53 by sustained JNK activation during apoptosis. 1110 63

Somatostatin, or its structural analog SMS 201-995 (SMS), is recognized to exert a growth-inhibitory action in rat pancreas, but the cellular mechanisms are not completely understood. This study was undertaken to evaluate the effect of SMS on p42/p44 MAP kinases and phosphatidylinositol 3-kinase activation and to analyze expression of some cell cycle regulatory proteins in relation to pancreatic acinar cell proliferation in vivo (rat pancreas), as well as in the well-established tumoral cell line AR4-2J. We herein report that: 1) SMS inhibits caerulein-induced pancreatic weight and DNA content and abolishes epidermal growth factor (EGF)-stimulated AR4-2J proliferation; 2) SMS only moderately reduces the stimulatory effect of caerulein on p42/p44 MAP kinase activities in pancreas and has no effect on EGF-stimulated MAP kinase activities in AR4-2J cells; 3) SMS repressed caerulein-induced Akt activity in normal pancreas; 4) SMS has a strong inhibitory action on cyclin E expression induced by caerulein in pancreas and EGF in AR4-2J cells and as expected, the resulting cyclin E-associated cyclin-dependent kinase (cdk)2 activity, as well as pRb phosphorylation, are blunted by SMS treatment in both models; and 5) SMS suppresses mitogen-induced p27(Kip1) down-regulation, as well as marginally induces p21(Cip) expression. Thus, our data suggest that somatostatin-induced growth arrest is mediated by inhibition of phosphatidylinositol 3-kinase pathway and by enhanced expression of p21(Cip) and p27(Kip1), leading to repression of pRb phosphorylation and cyclin E-cdk2 complex activity.
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PMID:Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells. 1114 74

The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-beta (TGF-beta) results in induction of tolerance, rendering alloreactive murine CD4(+) T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-beta-tolerant CD4(+) T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G(1) phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFbeta + IL-10-tolerant cells were incapable of phosphorylating TCR-zeta, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27(kip1) cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-beta-tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.
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PMID:Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease. 1115 38

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18


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