Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the role of mitogen-activated protein (MAP) kinases in the signal transduction of basic fibroblast growth factor (bFGF)-mediated effects in endothelial cells (ECs). When MSS31 murine endothelial cells were stimulated with bFGF, three MAP kinase homologs, extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) 1, and p38 MAP kinase were activated. The inhibition of the ERK1/2 pathway with PD98059, a specific inhibitor of MEK1, or of the p38 MAP kinase pathway with SB203580, a specific inhibitor of p38 MAP kinase, abrogated bFGF-mediated tube formation by MSS31 cells in type I collagen gel. Tube formation in type I collagen gel requires proliferation and migration of these cells, and degradation of the extracellular matrix by these cells. Both PD98059 and SB203580 inhibited bFGF-stimulated DNA synthesis as well as migration of MSS31 cells. Cell migration requires cytoskeleton reorganization and cell adhesion. bFGF induced actin reorganization and vinculin assembly in the focal adhesion plaque, both of which were inhibited by SB203580 but not by PD98059. bFGF induced the expression of the transcription factor ETS-1 in MSS31 cells. ETS-1 is responsible for the expression of proteases as well as integrin beta 3 subunit in ECs, and converts ECs to invasive phenotype. PD98059 inhibited this induction of ETS-1, whereas SB203580 did not. These results indicate that ERK1/2 and p38 MAP kinase are requisite for the signal transduction of bFGF in ECs. The roles of these two MAP kinase homologs are not identical, but these kinases work in a coordinated fashion.
Jpn J Cancer Res 1999 Jun
PMID:Roles of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in the signal transduction of basic fibroblast growth factor in endothelial cells during angiogenesis. 1042 57

Stimulation of mitogen-activated protein kinases (MAPKs) or extracellular signal regulated protein kinases (ERKs) after exposure of mammalian cells to ultraviolet (UV) and X-irradiation occurs through activation of receptor tyrosine kinases via Ras/Raf/Mek/ERKs cascade. This activation of MAPKs is proposed to play a role in the replacement of damaged proteins during these stresses. Heat shock also activates MAPKs; however, the signaling cascade and the biochemical and physiological links between activation by heat and downstream effects are unknown. In this report we demonstrate that, unlike irradiation, heat induces MAPKs through ceramide metabolism to sphingosine with stimulation of Raf-1 protein kinase. The activation of MAPKs by heat does not occur in all cell types, because the step(s) downstream of ceramide to activation of Raf-1 protein kinase is missing in myeloid leukemic cells such as HL-60, U937, and K562, while it is present in NIH3T3 fibroblasts. Heat-induced MAPK activation may enhance the ability of cells to survive a severe heat shock. Blocking 60-70% of the activity of MAPK (ERK1) by stable overexpression of the dominant negative allele ERK1-KR renders NIH3T3 and K562 cells up to 100-fold more sensitive to cytotoxic effects of heat. Conversely, NIH3T3 and K562 cells stably overexpressing the wild-type ERK1 develop resistance to killing by heat. These results suggest that increased thermal sensitivity of leukemic cells to thermal stress or other cancer therapy regimens could be attributable to lack of pertinent activation of the MAPK pathway by such stresses.
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PMID:An essential role for mitogen-activated protein kinases, ERKs, in preventing heat-induced cell death. 1044 Sep 34

Protein phosphorylation is the major post-translational modification used by eukaryotic cells to control cellular signaling. Protein kinases have emerged as attractive drug targets because heightened protein kinase activity has been associated with several proliferative diseases, most notably cancer and restenosis. Until now, it has been very difficult to confirm the utility of protein kinases as inhibitor targets because very few small molecules that selectively inhibit one particular kinase are known. Discovery of highly specific kinase inhibitors has been slow because the protein family contains approximately 2000 members, all of which share a conserved active site fold. Recent work in several laboratories has sought to circumvent the problem of kinase structural degeneracy by engineering drug sensitivity into Src family tyrosine kinases and mitogen-activated protein kinases through site-directed mutagenesis. By introducing a unique non-naturally occurring amino acid into a conserved region of the enzyme's binding site, a target protein kinase can be rapidly sensitized to a small molecule. Introduction of the engineered kinase into a cell line or animal model should greatly expedite the investigation of protein kinase inhibition as a viable drug treatment. The purpose of this review is to summarize these recent advances in protein kinase drug sensitization.
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PMID:Acquisition of inhibitor-sensitive protein kinases through protein design. 1045 10

WAVE is a Wiskott-Aldrich syndrome protein (WASP)-family protein that functions in membrane-ruffling formation induced by Rac, a Rho family small GTPase. Here we report that WAVE is a phosphoprotein whose phosphorylation increases in response to various external stimuli that activate mitogen-activated protein (MAP) kinase signaling. When Swiss 3T3 cells are stimulated with platelet-derived growth factor, electrophoretic mobility shift occurs to WAVE, which reflects hyperphosphorylation. This is perfectly inhibited by the addition of PD98059, a specific inhibitor of MAP kinase kinase. Indeed, the ectopic expression of an activated mutant of MAP kinase kinase induces WAVE mobility shift. When MAP kinase activation is suppressed by PD98059, the intensity of platelet-derived growth factor-induced membrane ruffling is greatly reduced. In various cancer cell lines, the amount of WAVE mobility shift was found to increase significantly, suggesting the importance of WAVE hyperphosphorylation in the formation of membrane ruffles and oncogenic transformation.
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PMID:Phosphorylation of WAVE downstream of mitogen-activated protein kinase signaling. 1048 99

Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3beta (GSK-3beta)-dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3beta. Phosphorylation of AKT and GSK-3beta by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta.
Cancer Res 1999 Sep 15
PMID:Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells. 1049 95

Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.
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PMID:In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. 1049 20

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor important for colon cancer neovascularization. In previous studies, serum starvation led to induction of VEGF in human colon carcinoma cells. We investigated the possible participation of mitogen-activated protein kinases in serum starvation induction of VEGF in the HT29 human colon carcinoma cell line. The extracellular signal-regulated kinases (Erks) 1 and 2 were activated after 3-6 h of serum starvation. Using transient transfection of VEGF promoter-reporter constructs, serum starvation led to an increase in VEGF promoter activity. An inhibitor of phosphorylation of Erk-1/2 blocked the increase of VEGF expression and promoter activity induced by serum starvation. Serum starvation activates several mitogen-activated protein kinases, but activation of Erk-1/2 is critical for the up-regulation of VEGF mRNA in colon carcinoma cells.
Cancer Res 1999 Oct 01
PMID:Extracellular signal-regulated kinase activation is required for up-regulation of vascular endothelial growth factor by serum starvation in human colon carcinoma cells. 1051 88

We have previously shown that inhibition of MCF-7 cell proliferation by 1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET-18-OCH3) is linked to a drug-induced decrease in membrane Raf-1 levels and the subsequent inhibition of mitogen-activated protein (MAP) kinase activation in response to growth factor stimulation. We now report that adaptation of MCF-7 cells for growth in a serum-free formulation results in decreased sensitivity to growth inhibition by ET-18-OCH3. The decrease in ET-18-OCH3 sensitivity occurred progressively during the adaptation process and correlated with the presence of increasing amounts of inactive Raf-1 that stably associated with MCF-7 cell membranes. ET-18-OCH3 sensitivity could be restored by growing the adapted cells in serum-containing medium, which resulted in the loss of membrane-associated Raf-1. In human normal mammary epithelial cells, which are insensitive to ET-18-OCH3, Raf-1 was also associated with membranes in quiescent cells. In both cell types, incubation with ET-18-OCH3 had no effect on the membrane-Raf-1 levels, suggesting that ET-18-OCH3-induced reduction of Raf-1 levels in growth factor-stimulated MCF-7 cells is due to inhibition of Raf translocation. The activation and termination of the MAP kinase pathway in response to growth factors in the adapted MCF-7 cells and HNME cells occurred without changes to membrane Raf-1 levels. Because membrane translocation is not required to activate Raf in these cells, inhibition of Raf translocation by ET-18-OCH3 subsequent to cell stimulation has no effect on the activation of the membrane-bound Raf and, consequently, the activation of the MAP kinase pathway. The ability of the cells to activate the MAP kinase pathway in the presence of the drugs enables them to resist the growth-inhibitory effects of the drug, leading to the observed ET-18-OCH3 insensitivity of the cells.
Cancer Res 1999 Oct 01
PMID:Decreased sensitivity to 1-O-octadecyl-2-O-methyl-glycerophosphocholine in MCF-7 cells adapted for serum-free growth correlates with constitutive association of Raf-1 with cellular membranes. 1051 89

Although gonadotropin-releasing hormone agonists (GnRHa) have been used in the therapy of the endocrine-dependent cancers, their biological mechanism remained obscure. We have studied the roles of mitogen-activated protein kinase family in the antiproliferative effect of GnRHa on the Caov-3 human ovarian cancer cell line. Reverse transcription-PCR assays confirmed mRNA for GnRH receptor in Caov-3 cells. In the presence of 1 microM GnRHa, the proliferation of cells was significantly reduced to 76% of controls after 24 h, and the effect was sustained up to 4 days. Although GnRHa had no effect on the activation of the Jun N-terminal kinase (JNK), treatment of Caov-3 cells with GnRHa activated extracellular signal-regulated protein kinase (ERK), and its effect was more than that induced by GnRH. Activation of ERK by GnRHa occurred within 5 min, with the maximum occurring at 3 h and sustained until 24 h. GnRHa also activated ERK kinase (mitogen-activated protein/ERK kinase) and resulted in an increase in phosphorylation of son of sevenless (Sos), and Shc. Furthermore, we examined the mechanism by which GnRHa induced ERK activation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, blocked the GnRHa-induced ERK activation. Phorbol 12-myristate 13-acetate (PMA) also induced the ERK activity, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the activation of ERK by GnRHa. Elimination of extracellular Ca2+ by EGTA also did not abolish the activation of ERK by GnRHa. To examine the role of ERK cascade in the antiproliferative effect of GnRHa, PD98059, an inhibitor of mitogen-activated protein/ERK kinase, was used. This inhibitor canceled the antiproliferative effect of GnRHa and apparently reversed the GnRH-induced dephosphorylation of the retinoblastoma protein, the hyperphosphorylation of which is a hallmark of G1-S transition in the cell cycle. These results provide evidence that GnRHa stimulation of ERK activity may be mediated by Gbetagamma protein, not by PMA-sensitive protein kinase C nor extracellular Ca2+ in the Caov-3 human ovarian cancer cell line, suggesting that this cascade may play an important role in the antiproliferative effect of GnRHa.
Cancer Res 1999 Oct 15
PMID:Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line. 1053 88

MDA-MB-231 cells are highly metastatic breast tumor cells. Their high invasiveness is thought to be due to constitutively high levels of urokinase-type plasminogen activator (uPA) and its receptor. Previously (R. Nanbu et al., C. Eur. J. Biochem., 247: 169-174, 1997), we showed that uPA mRNA in these cells is stable and that mRNA degradation mediated by an AU-rich element (ARE) is impaired. Here we report that treatment of MDA-MB-231 cells with SB203580, an inhibitor of the stress-activated p38 mitogen-activated protein (MAP) kinase, strongly destabilized uPA mRNA in an ARE-dependent manner. In contrast, in LLC-PK1 and HeLa cells, uPA mRNA is unstable, and an ARE present in the 3' untranslated region plays a role in its degradation. Enhanced ARE-mediated mRNA destabilization induced by SB203580 was also observed in both LLC-PK1 and HeLa cells with a globin chimeric mRNA harboring two copies of the ARE (globin-2ARE) from uPA mRNA. Overexpression of constitutively active MKK6, a p38 upstream activator kinase, increased the stability of the globin-2ARE message in LLC-PK1 cells, confirming the participation of p38 in the regulation of ARE-mediated mRNA decay. Interestingly, the half-life of the uPA mRNA in the three cell lines studied correlated with the basal levels of active p38. SB203580 treatment of MDA-MB-231 cells decreased cell-associated uPA activity and dramatically reduced in vitro cell invasiveness. These results suggest the participation of p38 in the control of invasiveness through regulation of the stability of uPA and uPA receptor mRNA, which is also destabilized by p38.
Cancer Res 1999 Oct 15
PMID:Regulation by p38 mitogen-activated protein kinase of adenylate- and uridylate-rich element-mediated urokinase-type plasminogen activator (uPA) messenger RNA stability and uPA-dependent in vitro cell invasion. 1053 11


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