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)

Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and beta-catenin signaling in mast cell leukemia. Beta-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. Beta-catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.
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PMID:KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia. 1794 10

Growth, survival and differentiation of hematopoietic cells are regulated by the interactions between hematopoietic growth factors and their receptors. The defect in these interactions results in a failure of hematopoiesis, while aberrantly elevated and/or sustained activation of these signals cause hematologic malignancies. Among them, constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c-Kit, platelet-derived growth factor receptor (PDGFR) and FLT3, are often involved in the pathogenesis of various types of hematologic malignancies. Constitutive activation of RTKs is provoked by several mechanisms including chromosomal translocations and various mutations involving their regulatory regions. Chromosomal translocations commonly generate chimeric proteins consisting of the cytoplasmic domain of RTKs and the dimerization or multimerization motif of the fusion partner, resulting in the constitutive dimerization of RTKs. On the other hand, missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop, and extracellular domain, also cause constitutive activation of RTKs mainly by preventing the auto-inhibitory regulation. Oncogenic RTKs activate downstream signaling molecules such as Ras/MAPK, PI3-K/Akt/mTOR, and STATs as well as ligand-activated wild type RTKs. However, their signals are quantitatively and qualitatively different from wild type RTKs. Based on these findings, several agents that target oncogenic RTKs or their downstream molecules have been developed: imatinib and FLT3 inhibitors for RTKs themselves, farnesyltransferase inhibitors, mTOR inhibitors and MEK inhibitors for the downstream signaling molecules. As promising results have been obtained in several clinical trials using these agents, the establishment of these molecular targeted agents is expected.
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PMID:Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies. 1817 85

Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7 vs 65.3 years) and is associated with longer median overall survival (11.1 vs 1.3 months; P<0.001). 14q32 (IgH) translocations are highly prevalent in both sPCL and pPCL (82-87%); in pPCL IgH translocations almost exclusively involve 11q13 (CCND1), supporting a central etiological role, while in sPCL multiple partner oncogenes are involved, including 11q13, 4p16 (FGFR3/MMSET) and 16q23 (MAF), recapitulating MM. Both show ubiquitous inactivation of TP53 (pPCL 56%; sPCL 83%) by coding mutation or 17p13 deletion; complemented by p14ARF epigenetic silencing in sPCL (29%). Both show frequent N-RAS or K-RAS mutation. Poor survival in pPCL was predicted by MYC translocation (P=0.006). Survival in sPCL was consistently short. Overall pPCL and sPCL are different disorders with distinct natural histories, genetics and survival.
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PMID:Genetic aberrations and survival in plasma cell leukemia. 1821 67

The hallmark of acute promyelocytic leukaemia (APL) is the reciprocal translocation t(15;17), which leads to the expression of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARalpha is directly targeted by all-trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARalpha, together with the constitutive activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) signalling pathway, regulates the ability of haematopoietic cells to proliferate, differentiate, and escape from apoptotic episodes. The role of the MEK/ERK pathway in PML/RARalpha expression, differentiation, proliferation and apoptosis in APL cells was analysed using specific MEK inhibitors. The blockade of MEK/ERK pathway resulted in caspase-dependent degradation of PML/RARalpha, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARalpha was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARalpha and exhibited a convergence point in caspase activation with MEK inhibitors. Taken together, our data suggest a new role of MEK/ERK pathway in the pathogenesis of APL, thus supporting the use of MEK/ERK inhibitors as an efficient therapeutic strategy for this haematological malignancy.
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PMID:MEK inhibition induces caspases activation, differentiation blockade and PML/RARalpha degradation in acute promyelocytic leukaemia. 1844 86

Activating mutations of FLT3 are found in approximately one-third of acute myeloid leukemia (AML)-cases and are considered to represent an attractive therapeutic target. In this study, we report that the hydroxystyryl-acrylonitrile compound LS104 inhibits proliferation and induces potent cytotoxic effects in FLT3 expressing leukemic cells in vitro. Immunoblot and phosphoprotein-FACS analysis demonstrated inhibiton of phosphorylation of FLT3-ITD and of its downstream targets. In pharmacokinetic studies, a rapid and dose dependent cellular uptake of LS104 lasting up to 11h could be demonstrated. Combination of LS104 with chemotherapeutic agents markedly enhanced cytotoxic effects. Recently, a phase I clinical trial investigating LS104 in refractory/relapsed hematologic malignancies has been initiated.
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PMID:The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia. 1855 63

Eosinophilia is a recurrent feature and diagnostic clue in several hematologic malignancies. In stem cell- and myelopoietic neoplasms, eosinophils are derived from the malignant clone, whereas in lymphoid neoplasms and reactive states, eosinophilia is usually triggered by eosinopoietic cytokines. Myeloid neoplasms typically presenting with eosinophilia include chronic myeloid leukemia, chronic eosinophilic leukemia (CEL), other myeloproliferative neoplasms, some acute leukemias, advanced mast cell disorders, and rare forms of myelodysplastic syndromes. Diagnostic evaluations in unexplained eosinophilia have to take these diagnoses into account. In such patients, a thorough hematologic work-up including bone marrow histology and immunohistochemistry, cytogenetics, molecular markers, and a complete staging of potentially affected organ systems has to be initiated. Endomyocardial fibrosis, the most dangerous cardiovascular complication of the hypereosinophilic state, is frequently detected in PDGFR-mutated neoplasms, specifically in FIP1L1/PDGFRA+ CEL, but is usually not seen in other myeloid neoplasms or reactive eosinophilia, even if eosinophilia is recorded for many years. Treatment of hypereosinophilic patients depends on the variant of disease, presence of end organ damage, molecular targets, and the overall situation in each case. In a group of patients, oncogenic tyrosine kinases (TK) such as FIP1L1/PDGFRA, can be employed as therapeutic targets by using imatinib or other TK-blocking agents.
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PMID:Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. 1924 39

According to the 2008 World Health Organization classification system for hematologic malignancies, the myeloproliferative neoplasms (MPN) include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, mastocytosis, chronic eosinophilic leukemia-not otherwise specified, chronic neutrophilic leukemia, and "MPN, unclassifiable." All of these clinicopathologic entities are characterized by stem cell-derived clonal myeloproliferation, and their phenotypic diversity is ascribed to the occurrence of distinct oncogenic events. In the last 4 years, new JAK2 and MPL mutations have been added to previously described ABL and KIT mutations as molecular markers of disease in MPN. These discoveries have markedly simplified the approach to clinical diagnosis and have also provided molecular targets for the development of small-molecule drugs. In the current article, the authors provide a clinically oriented overview of MPNs in terms of their molecular pathogenesis, classification, diagnosis, and management.
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PMID:Advances in understanding and management of myeloproliferative neoplasms. 1936 82

Wilms's tumor gene (WT1) is overexpressed in a variety of hematologic malignancies and solid tumors. Recently, WT1 protein has been considered as a molecular target of cancer immunotherapy for several solid tumors and as a tool for monitoring minimal residual disease in leukemia patients. There are only few investigations on WT1 expression in central nervous system neoplasms, which suggest that the WT1 gene may play an important role in tumorigenesis of primary astrocytic tumors and that high-grade tumors express high levels of WT1 proteins. We examined 50 low-grade and high-grade gliomas using tissue microarray and immunohistochemical methods to identify WT1 protein, P53, Ki-67, GFAP, NFP, EGFR, nestin, and Neu-N expression. WT1 and nestin shared overlapping expression in all gliomas and were increased in high-grade examples, highlighting their potential use as diagnostic and prognostic tumor markers. Our results support the combined role of WT1 and nestin in glial tumorigenesis and progression.
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PMID:High-grade astrocytomas show increased Nestin and Wilms's tumor gene (WT1) protein expression. 1957 47

Rap1 is a small G protein belonging to the RAS superfamily. Rap1 signalling has effects on cell growth, cell proliferation and involves in regulation of the mitogen activated protein (MAP) kinase or ERK (extracellular signal regulated kinase) cascade. Rap1 will directly activate ERK through B-Raf. B-Raf is a member of Raf family, and presents in neuronal and hematopoietic cells. Oncogenic mutations of gene RAS are most frequent and detected in 20% - 30% of human leukemias and 10% - 15% of MDS cases. The review summarizes the regulatory function of Rap1 in development of hematopoietic cells and effect of Rap1 in hematologic malignancies.
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PMID:Regulatory function and expression of rap1gap gene in hematopoietic cells-review. 1969 68

The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.
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PMID:GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. 1982 1


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