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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported a constitutively activated form of the Flt-1 kinase (BCR-FLTm) molecularly engineered based on the structural backbone of the activated tyrosine kinase BCR-ABL. Here we show that it can induce not only growth stimulation but also tubulogenic differentiation of non-tubulogenic NP31 (non parenchymal) sinusoidal endothelial cells of rat liver in basement membrane matrix. Tubules formed in vitro were accompanied by fenestration structures and allowed circulation when transplanted into syngeneic animals. This biological response was not observed in other activated forms of kinases constructed in a similar fashion, which include Trk (BCR-TRK), KDR (BCR-KDR), and the parental BCR-ABL. Interestingly, formation of fine tubules was accomplished with lower but not higher expression levels of BCR-FLTm. Compared to NP cells in primary culture NP31 is deficient in expression of alpha1 integrin subunit, which was restored by expression of BCR-FLTm that had tubulogenic ability. Matrix-induced tyrosine phosphorylation of an adaptor protein Shc with recruitment of Grb-2 was observed even when tubulogenesis was nearly completed at G1 stage of the cell cycle in 2-3 weeks. Activation of matrix metalloproteinase 2 (MMP-2) and expression of urokinase type plasminogen activator (uPA) was observed with cellular invasion into matrix at the depth of 200-300 microm. Inhibitors for MAP kinase activator MEK1 and for serine proteases showed deleterious effects on the tubulogenesis. We suppose that matrix ligand-induced integrin signals cooperate with a low level of Flt-1 kinase activity to promote tubulogenic behaviors of endothelial cells in this system.
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PMID:An oncogenic form of the Flt-1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line. 1072 21

Disruption of the RAS-to-mitogen-activated protein kinase (MAPK/ERK) signaling pathway, either directly through activating RAS gene mutations or indirectly through other genetic aberrations, plays an important role in the molecular pathogenesis of myeloid leukemias. Constitutive activation of ERK-1/2 and MEK-1/2, which elicit oncogenic transformation in fibroblasts, has recently been observed in acute myeloid leukemias (AML). In this study, the activation of the RAS-to-MAPK cascade in 14 AML and 5 chronic myeloid leukemia (CML) cell lines is examined and correlated with the effects of a panel of 9 RAS signaling inhibitors on cell viability, colony formation, cell-cycle progression, and induction of apoptosis. Activation of MEK, ERK, and the transcription factors CREB-1, ATF-1, and c-Myc is demonstrated in the majority of the cell lines (9 of 14 AML and 2 of 5 CML cell lines). Although activation of the ERK cascade did not always correlate with the presence of activating RAS mutations or BCR-Abl, it is linked to the G0/G1 and the G2/M phase of the cell cycle. In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met, FPT-2, FTI-276, and FTS), a significant growth inhibition was only observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK inhibitors U0126 (19 of 19) and PD098059 (8 of 19). Treatment of NB-4 cells with FTI-277 primarily resulted in a G2/M block, whereas treatment with FPT-3 and U0126 led to induction of apoptosis. FTI-277 revealed strong toxicity toward normal purified CD34+ cells. The results suggest differences in the mechanisms of action and support a potential therapeutic usefulness of these inhibitors in the treatment of myeloid leukemias.
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PMID:Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. 1123 26

Inhibition of signaling through Ras in BCR-ABL-positive pluripotent K562 cells leads to apoptosis and spontaneous differentiation. However, Ras-induced activation of the mitogen-activated protein kinase ERK has been suggested to play a critical role in either growth or differentiation in different model systems. We studied the role of ERK activation in the growth-promoting and anti-apoptotic effect of Ras and its involvement in hemin-induced nonterminal erythroid differentiation using the BCR-ABL-positive K562 cell line as a model. K562 cells were stably transfected with ERK1 or the dominant inhibitory mutant of ERK1 (ERK1-KR). Overexpression of ERK1-KR inhibited cell growth with an approximately fourfold increase in doubling time and induced apoptosis in K562 cells. Incubation with the MEK1 inhibitor UO126 inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner as well. In the presence of exogenously added hemin, K562 cells differentiate into erythroblasts, as indicated by the production of large amounts of fetal hemoglobin. We examined the activation of MAP kinases during hemin-induced differentiation. The ERK1 and 2 activity increased within 2 h post hemin treatment and remained elevated for 24-48 h. During this time, fetal hemoglobin synthesis also increases from 0.8 to 10 pg/cell. There was no activation of JNK or p38 protein kinases. The hemin-induced accumulation of hemoglobin was inhibited in ERK1-KR overexpressing cells and was enhanced in the wild-type ERK1 transfectants. Our results suggest that ERK activation is involved in both growth and hemin-induced erythroid differentiation in the BCR-ABL-positive K562 cell line.
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PMID:Role of ERK activation in growth and erythroid differentiation of K562 cells. 1126 76

Tyrosine kinase inhibitors have drawn the most attention in recent years as molecular target agents for cancer treatment. The reason for this can only be the dramatic antitumor effects shown in early clinical trials against small cell cancer and chronic myeloid leukemia by the EGFR tyrosine kinase inhibitor, ZD1839, and the BCR-Abl tyrosine kinase inhibitor, STI-571, respectively. Various hypotheses were advanced in the preliminary stages of the clinical development of such molecular target agents: "They only prevent cancer cell proliferation and have no killer cell activity; they are extremely weak, and can not be expected to reduce tumors at the clinical level. "Or:" A long time is required before their physiological activity will be expressed in an antitumor effect." However, with non-small cell lung cancer, the most difficult tumor among solid cancers for an anticancer agent to be effective, not only was ZD1839 effective, but showed clear effectiveness in combination chemotherapy in the pretreatment stage. Moreover, the time for the expression of its tumor reduction effect was virtually the same as with conventional anticancer drugs, and its effectiveness proved to last longer after its initial expression. ZD1839 has succeeded in remaking the very image of molecular target agents for cancer treatment. In what follows, we focus mainly on the EGFR tyrosine kinase inhibitor, ZD1839.
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PMID:[Tyrosine kinase inhibitors--solid cancers]. 1138 8

Gastrointestinal stromal tumor (GIST) has emerged in the past year as a prototypical neoplasm that responds to therapy directed against a single target molecule-the KIT receptor tyrosine kinase protein. Although GIST seldom responds to conventional chemotherapeutic agents, early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec; Novartis, Basel, Switzerland), has been extremely encouraging. Early results have appeared in a recent case report in the New England Journal of Medicine (April 5, 2001),(1) and in early clinical trials from the United States and Europe that were reported at the plenary session of the American Society of Clinical Oncology in San Francisco on May 14, 2001. STI-571 is one of the earliest examples of a nontoxic chemotherapeutic agent (an agent whose anti-cancer activity is not predicated on a cytotoxic mechanism). STI-571 has already shown clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571. To ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).
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PMID:Gastrointestinal stromal tumor workshop. 1143 11

Gastrointestinal stromal tumors (GISTs) are distinctive, KIT positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well known. In this study, we looked for recurrent numerical chromosomal changes, which may be associated with malignant GISTs, using interphase fluorescence in situ hybridization (FISH). Fourteen malignant primary tumors and two intra-abdominal recurrences were analyzed. Nine benign tumors were studied for comparison. In all cases, the presence of mutations in exons 9, 11 and 13 of the KIT gene were evaluated. Sixteen centromeric enumeration probes (CEP) for chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, and X and three locus specific probes (LSI) for 22q11.2 (BCR-locus), 13q14 (RB1-locus) and 14q32 (IgH-locus) were used. The most common changes seen in malignant GISTs were losses of 14q32 and 22q11. However, these changes were commonly detected in benign tumors and represent early changes related to the pathogenesis of GISTs. Losses of chromosomes 1 and 9 were the only recurrent numerical changes seen exclusively in malignant GISTs. Other recurrent numerical changes seen predominantly in malignant tumors were gain of chromosome 8 and losses of chromosomes 7 and 15. The concurrent loss of chromosome 7 and gain of chromosome 8 (in 4 cases) was never seen together with loss of chromosomes 9 or 15 and only once with loss of chromosome 1. Mutations in KIT were found in the majority of malignant GISTs (64%) confirming a previously shown correlation between presence of such mutations and malignancy. KIT mutations were seen in four of five malignant GISTs with loss of chromosome 9, but only in one of four malignant tumors with loss of chromosome 1. These observations may reflect the different pathways leading to malignant transformation of GISTs.
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PMID:Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation. 1145 25

B lymphocytes from mice null for the Rho-family guanine-nucleotide exchange factor, Vav, are defective in their ability to proliferate in response to BCR cross-linking, but are able to proliferate normally in response to LPS. In addition, they have a depletion of CD5(+) (B1) lymphocytes and defective IgG class switching. This phenotype is reminiscent of that observed in mice null for the cell cycle regulatory protein, cyclin D2. We demonstrate here that the inability of vav(-/-) B cells to proliferate in response to BCR ligation is due to an inability to induce cyclin D2. In addition, we show that the proliferative defect of these cells occurs after the cells have entered early G1 phase. Analyses of potential down-stream signaling intermediates revealed differential activation of the stress-activated MAP kinases in the absence of Vav, normal activation of the ERK, MAPK, and phosphatidylinositol 3-kinase pathways, and defective intracellular calcium mobilization. We further demonstrate that intracellular calcium homeostasis is required for cyclin D2 induction, implicating a possible link with the defective calcium response of vav(-/-) B cells and their inability to induce cyclin D2.
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PMID:Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen Receptor. 1154 4

Fusion gene products such as PML-RARalpha and BCR-ABL generated by leukemia-specific chromosomal translocations have been identified as target molecules for the treatment of leukemia. Here we describe one possibility for extending the frontier of mechanism-based medicine for acute myeloid leukemia (AML). FLT3, a receptor tyrosine kinase (RTK) preferentially expressed in hematopoietic progenitor cells, frequently has a gain-of-function mutation in AML. To search for FLT3-targeted compounds, we screened the growth-inhibitory effects of several tyrosine kinase inhibitors (TKIs) on mutant FLT3-transformed 32D cells. Herbimycin A at a concentration of 0.1 microM markedly inhibited the growth of the transfectants but at that concentration was ineffective in parental 32D cells. It suppressed the constitutive tyrosine phosphorylation of the mutant FLT3, but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with transformed 32D cells, the administration of herbimycin A completely prevented leukemia progression. Recent studies have indicated that herbimycin A binds directly with HSP90, a molecular chaperone, and destabilizes HSP90-associated proteins. Another HSP90 inhibitor, radicicol, also induced apoptosis selectively in transformed 32D cells. HSP90 is a promising target for the treatment of AML with mutant FLT3.
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PMID:FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. 1158 62

Imatinib mesylate, also known as STI571 or CGP57148, is a competitive inhibitor of a few tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 300 mg or greater, the vast majority of patients with chronic myeloid leukaemia achieve a haematological response and this is usually associated with limited toxicity. Imatinib also has substantial activity in Philadelphia chromosome-positive acute lymphoblastic leukaemia expressing the BCR-ABL fusion protein. Gastrointestinal stromal tumours (GISTs) have also been evaluated for clinical activity of imatinib. About 90% of malignant GISTs harbour a mutation in c-kit leading to KIT receptor autophosphorylation and ligand-independent activation. According to initial clinical studies, more than 50% of GISTs respond to therapy within a few months, and only about 10-15% progress. The potential for cure and the optimal length of treatment are currently not known. Several other human cancers may over-express KIT or PDGF-R, and clinical trials to evaluate the role of imatinib in the treatment of such cancers are currently ongoing. Imatinib is an example of a specifically designed, highly targeted cancer therapy, which poses novel requirements for both pathology laboratories and clinicians in terms of identifying the major molecular mechanisms involved in tumour growth.
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PMID:Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. 1168 Jul 92

Several recurrent translocations that involve chromosome band 8p11 have been described in myeloid malignancies. These translocations target two distinct genes: (1) FGFR1, a receptor tyrosine kinase for fibroblast growth factors, and (2) MOZ, a putative histone acetyltransferase whose precise function remains to be defined. Disruption of FGFR1 is associated with a disease entity known as the 8p11 myeloproliferative syndrome (EMS)/stem cell leukemia-lymphoma syndrome, a chronic myeloproliferative disorder that frequently presents with eosinophilia and associated T-cell lymphoblastic lymphoma. The disease is aggressive and rapidly transforms to acute leukaemia, usually of myeloid phenotype. Currently, only allogeneic stem cell transplantation appears to be effective in eradicating or suppressing the malignant clone. To date, four gene fusions associated with distinct translocations have been described in EMS: the t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11q22) fuse ZNF198, CEP110, FOP and BCR, respectively, to FGFR1. The resulting fusion proteins have constitutive tyrosine kinase activity and activate multiple signal transduction pathways. These pathways and the fusion proteins are attractive targets for targeted signal transduction therapy.
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PMID:The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. 1191 91


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