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 analyzed tandem duplication in the juxtamembrane (JM) domain of the FLT3 (FMS-like tyrosine kinase 3/FLK2, CD135) gene in 94 children with acute myeloid leukemia (AML) and evaluated its correlation with clinical features. Longer polymerase chain reaction (PCR) products were observed in five patients; 1/3 of M0, 119 of M1, 1/39 of M2, 1/9 of M3 and 1/12 of M5. The sequence analyses of abnormal PCR products showed that all the abnormal products were derived from tandem duplications involving the JM domain and that all the lengthened sequences were in-frame as we previously reported. Statistical analyses revealed a significantly lower incidence of the tandem duplication in childhood AML patients than in adult patients (P < 0.05), and significantly shorter disease-free survival in patients with mutant FLT3 than in patients with wild-type FLT3 (P < 0.05). Our results suggest that the tandem duplication in the JM domain of the FLT3 gene is not a frequent phenomenon but might be a factor of poor prognosis in childhood patients with AML.
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PMID:Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. 1004 58

Mutations are defined as stable and irreversible modifications of the normal genetic message due to small changes in the number or type of bases, or to large modifications of the genome such as deletions, insertions or chromosome rearrangements. These lesions are due to either polymerase errors during normal DNA replication or unrepaired DNA lesions, which will give rise to mutations through a mutagenic pathway. The molecular process leading to mutagenesis depends largely on the type of DNA lesions. Base modifications, such as 8-oxo-guanine or thymine glycol, both induced by ionizing radiations (IR), are readily replicated leading to direct mutations, usually base-pair substitutions. The 8-oxo-G gives rise predominantly to G to T transversions, the type of mutations found in ras or p53 gene from IR-induced tumors. Bulky adducts produced by chemical carcinogens or UV-irradiation are usually repaired by the nucleotide excision repair (NER) pathway which is able to detect structural distortion in the normal double-strand DNA backbone. These lesions represent a blockage to DNA and RNA polymerases as well as some signal for p53 accumulation in the damaged cell. In the absence of repair, these lesions could be eventually replicated owing to the induction of specific proteins at least in bacteria during the SOS process. The precise nature of the error-prone replication across an unexcised DNA lesion in the template is not fully understood in detailed biochemical terms, in mammalian cells. IR basically produce a very large number of DNA lesions from unique base modifications to single- or double-strand breaks and even complex DNA lesions due to the passage of very high energy particles or to a local re-emission of numerous radicals. The breakage of the double-helix is a difficult lesion to repair. Either it will result in cell death or, after an incorrect recombinational pathway, it will induce frameshifts, large deletions or chromosomal rearrangements. Most of the IR-induced mutations are recessive ones, requiring therefore a second genetic event in order to exhibit any harmful effect and a long latency period before the development of a radiation-induced tumor. The fact that IR essentially induced deletions and chromosomal translocations renders very difficult the use of the p53 gene as a marker for mutation analysis. In agreement with the type of lesions induced by IR, it is interesting to point out that the presence has been observed, in a vast majority of radiation-induced papillary thyroid carcinomas (PTC), of an activated ret proto-oncogene originated by the fusion of the tyrosine kinase 3' domain of this gene with the 5' domain of four different genes. These ret chimeric genes which are due to intra- or inter-chromosomal translocations, were called RET/PTC1 to PTC5. The RET/PTC rearrangements were found in PTC from children contaminated by the Chernobyl fall-out as well as in tumours from patients with a history of therapeutic external radiation, with a frequency of 60-84%. This frequency was only 15% in 'spontaneous' PTC. The type of ret chimeric gene predominantly originated by the accidental or therapeutic IR was different. Indeed, PTC1 was present in 75% of the tumours linked to a therapeutic radiation and PTC3 in 75% of the Chernobyl ones. The other forms of RET/PTC were observed in only a minority of the post-Chernobyl PTC (< 20%). The difference in the frequency of PTC1 and PTC3 in both types of PTC, is statistically significant (P < 10(-5), Fischer's exact test). In two of the post-therapeutic radiation PTC, RET/PTC1 and PTC3 were simultaneously present. A PTC1 gene was also observed in 45% of the adenomas appearing after therapeutic radiation. The long-period of latency between exposure to IR and the appearance of thyroid tumours is probably due to the conversion of a heterozygote genotype of IR-induced mutations to a homozygote one. It will be interesting to use this time lag in accidental or therapeutic-irradiated p
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PMID:Mechanisms of mutagenesis in mammalian cells. Application to human thyroid tumours. 1019 66

The molecular mechanism of carcinogenesis is a multistep process that is characterized by both activation of oncogenes and inactivation of tumor suppressor genes. In the present study, mutations of N-ras, p53 and FMS-like tyrosine kinase 3 (FLT-3) genes and loss of expression of the deleted in colorectal carcinoma (DCC) gene were analyzed in 59 patients with myelodysplastic syndromes (MDS). Mutations of N-ras, p53, and FLT-3 genes were detected in 7, 7, 1 of the 59 patients with MDS, respectively. Loss of DCC expression was detected in 16 patients. Type of MDS patients with N-ras mutation were all refractory anemia with excess of blasts in transformation (RAEB-T). Abnormalities of p53 and DCC genes were significantly associated with survival time (p< 0.02, p< 0.004, respectively).
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PMID:[Abnormalities of the p53, N-ras, DCC and FLT-3 genes in myelodysplastic syndromes]. 1130 59

The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.
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PMID:Molecular analysis of single colonies reveals a diverse origin of initial clonal proliferation in B-precursor acute lymphoblastic leukemia that can precede the t(12;21) translocation. 1173 41

Dendritic cells (DCs) are the major cells responsible for the uptake and the transport of antigens to regional lymphoid tissues and for the presentation of antigenic peptides to T cells. They are highly effective in immunotherapy. However, in lymphoid and other tissues, DCs constitute only a small population and are difficult to isolate in large numbers. Our objective was to devise a method with which to rapidly expand splenic DCs in vivo. We accomplished this by intramuscular injection of plasmids encoding mouse granulocyte-macrophage colony stimulating factor (GM-CSF) and fms-like tyrosine kinase 3-ligand (FLT3-L). Gene transfer was amplified by electroporation. Both cytokine vectors significantly increased DC numbers, but they were more effective in combination. When either control plasmid (Blank), or FLT3-L or GM-CSF expression plasmids were injected individually, the mean numbers of CD11c(+)/MHC II(+) DCs in spleen cell suspensions were, respectively, 6, 11, and 23 million. When FLT3-L and GM-CSF plasmids were codelivered, this increased to 36 million. Peak levels occurred 7 days postinjection of DNA. To further characterize these DCs, we stained them with myeloid (CD11b, F4/80)- and lymphoid (CD8alpha)-related markers. FLT3-L cDNA favored lymphoid DC expansion and GM-CSF cDNA favored myeloid DC expansion, whereas combined treatment expanded both types with a myeloid predominance. We confirm the ability of these DCs to present antigen to CD4(+) T cells and to stimulate in mixed lymphocyte cultures. We demonstrate that DCs can be rapidly expanded by this simple gene transfer method, which has numerous potential applications.
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PMID:In vivo generation of dendritic cells by intramuscular codelivery of FLT3 ligand and GM-CSF plasmids. 1223 Nov 78

Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the type III RTK family. Given the conserved homology between members of this family, we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC(50)], 100 nM; and SU5614 IC(50) 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC(50), 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines. Treatment of these cells with an alternative growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.
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PMID:SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. 1235 6

Recovery from radiation-induced (RI) myelosuppression depends on hematopoietic stem and progenitor cell survival and the active proliferation/differentiation process, which requires early cytokine support. Single cytokine or late-acting growth factor therapy has proved to be inefficient in ensuring reconstitution after severe RI damage. This work was aimed at evaluating the in vivo survival effect of combinations of early-acting cytokines whose antiapoptotic activity has been demonstrated in vitro: stem cell factor (SCF [S]), FMS-like tyrosine kinase 3 ligand (FLT-3 ligand [F]), thrombopoietin (TPO [T]), interleukin-3 (IL-3 [3]), and stromal derived factor-1 (SDF-1). B6D2F1 mice underwent total body irradiation at 8 Gy cesium Cs 137 gamma radiation (ie, lethal dose 90% at 30 days) and were treated soon after irradiation, at 2 hours and at 24 hours, with recombinant murine cytokines, each given intraperitoneally at 50 microg/kg per injection. All treatments induced 30-day survival rates significantly higher than control (survival rate, 8.3%). 4F (SFT3) and 5F (4F + SDF-1) were the most efficient combinations (81.2% and 87.5%, respectively), which was better than 3F (SFT, 50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better than 4F given at 10 microg/kg per injection (4F10, 45.8%) or as a 50 microg/kg single injection at 2 hours (4Fs, 62.5%). Despite delayed death occurring mainly from day 150 on and possible long-term hematopoiesis impairment, half the 30-day protective effects of 4F and 5F were preserved at 300 days. Our results show that short- and long-term survival after irradiation depends on appropriate multiple cytokine combinations and at optimal concentrations. The proposal is made that an emergency cytokine regimen could be applied to nuclear accident victims as part of longer cytokine treatment, cell therapy, or both.
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PMID:Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival. 1246 35

Dendritic cells (DCs) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to alterations in DC homeostasis. Taken together, our results demonstrate profound alterations of DCs and DC-poietins homeostasis in SLE. Elevated levels of interferon-alpha (IFN) in serum of SLE patients coexist with decreased numbers of cells producing IFN-alpha, i.e., plasmacytoid dendritic cells (PDCs). Decreased numbers of circulating DCs correlate with increased levels of soluble tumor necrosis factor (TNF) receptors, thus suggesting the potential role of TNF pathway in the observed DC alterations. Finally, increased FMS-like tyrosine kinase 3-ligand (FLT3-L) and its correlation with soluble TNF receptors suggest a physiologic response to compensate low DC numbers. Although IFN-alpha remains at the center of immunologic aberrations in SLE, it remains to be determined whether increased shedding of soluble TNF receptors could also be ascribed to IFN-alpha.
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PMID:Blood dendritic cells and DC-poietins in systemic lupus erythematosus. 1248 Feb 61

Hepatocellular carcinoma is a common malignancy causing significant morbidity and mortality worldwide. In this study we use expression microarray technology to identify novel genes that consistently displayed altered expression levels in the earliest identifiable precursors to hepatocellular carcinoma, dysplastic and macroregenerative nodules. The gene expression profiles from nine patients with end-stage hepatitis C cirrhosis that contained a combined 11 dysplastic or macroregenerative nodules were compared to the patient's matched cirrhotic liver tissue. A total of 53 genes were consistently dysregulated in the patient liver specimens. Six of seven genes were validated by quantitative real-time reverse transcriptase-polymerase chain reaction, or by immunohistochemical studies performed on an independent set of lesions. The novel genes, including caveolin-1, semaphorin E, and FMS-like tyrosine kinase 3 ligand, have putative roles in carcinogenesis but have not been reported in hepatocellular carcinogenesis. Microarray expression analysis of dysplastic and macroregenerative liver nodules provide insight into the earliest changes in hepatocellular carcinogenesis.
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PMID:cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis. 1259 31

Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in approximately 25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.
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PMID:The role of FLT3 in haematopoietic malignancies. 1295 84


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