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)

The receptors for at least two hematopoietic growth factors, namely the stem cell factor and colony-stimulating factor 1, belong to class III receptor tyrosine kinases. Here we describe cloning of a partial complementary DNA for FLT4, an additional member of this gene family from human leukemia cells. The FLT4 tyrosine kinase domain is 79% homologous with the previously cloned FLT1 (M. Shibuya et al., Oncogene, 5: 519-524, 1990) tyrosine kinase and maps to the chromosomal region 5q33-qter. We have found FLT4 expression in human placenta, lung, heart, and kidney, whereas the pancreas and brain appeared to contain very little if any FLT4 RNA. The results suggest that FLT4 functions in multiple adult tissues.
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PMID:FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. 131 71

We have investigated whether point mutations occurred at codon 301 or 969 of FMS (M-CSF receptor) in 19 patients with acute myelomonocytic (M4) and monocytic leukemia (M5). Nineteen peripheral blood and bone marrow blood samples collected from M4 and M5 patients were examined by using polymerase chain reaction and hybridization to allele specific oligonucleotide probes. Mutations at codon 301 and 969 of FMS were not detected in any samples. FMS gene mutations at codon 301 and 969 were rarely involved in M4 and M5 patients in Japan.
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PMID:Rare point mutation at codon 301 and 969 of FMS/M-CSF receptor in acute myelomonocytic and monocytic leukemia. 138 36

Preleukemia is thought to be a clonal disorder of hemopoietic stem cells. The conversion of a normal cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. The myelodysplastic syndromes have become a paradigm for human preleukemia, where nonrandom chromosomal abnormalities, including complete or partial deletions of chromosomes five and seven, trisomy eight and Y chromosome loss suggest specific changes. Of particular significance are 5q deletions, as many genes important in hemopoiesis are located in this region, including the proto-oncogene FMS, which encodes the receptor for the macrophage colony-stimulating factor, CSF-1. Genetic damage such as point mutations in the RAS and FMS genes has been detected in preleukemia patients. The RAS gene family (N, K and H) encodes membrane-bound G proteins, which, like other proto-oncogenes, are components of the intracellular signal transduction pathways controlling mitogenesis and differentiation. The characterization of such lesions may ultimately identify those patients at greatest risk of leukemic transformation.
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PMID:Genetic lesions in preleukemia. 142 Apr 44

Retroviral vectors containing human FMS protooncogene cDNA were reconfigured to allow single-step excision and reinsertion of restriction fragments encoding short segments of the extracellular domain of the colony-stimulating factor 1 receptor (CSF-1R). Fragments ligated into M13 bacteriophages were subjected to random chemical mutagenesis on both strands and recloned into the parental vector to create libraries of FMS genes containing mutations restricted to predefined target cassettes. Transfection of retroviral vector libraries into NIH/3T3 cells gave rise to transformed foci from which cellular DNA was amplified by the polymerase chain reaction (PCR), using primers flanking the mutagenized target sequences. Amplified fragments from individual primary transformants were recloned into intact FMS vector plasmids, and those with transforming activity were subjected to nucleotide sequence analysis. Alternatively, retroviruses rescued from transformed cells by superinfection with helper virus were used to generate secondary transformants containing unique copies of proviral DNA, whose sequences were determined after PCR amplification. Novel activating mutations were identified within sequences separating the third and fourth immunoglobulin-like loops, as well as within non-covalently stabilized loop 4 of the CSF-1R extracellular domain. Thus, FMS mutations able to convert human CSF-1R to an active oncoprotein are not restricted to those previously identified at codon 301. This approach should be generally applicable for defining activating mutations in related growth factor receptors, including those for platelet-derived growth factor and Steel factor (KIT ligand), in which ligand-independent oncoprotein variants have not been identified.
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PMID:Random mutagenesis of CSF-1 receptor (FMS) reveals multiple sites for activating mutations within the extracellular domain. 153 31

The MET proto-oncogene encodes a transmembrane tyrosine kinase receptor for HGF (p190MET). In this work, p190MET was immunoprecipitated, allowed to phosphorylate in the presence of [gamma-32P]ATP, and digested with trypsin. A major phosphopeptide was purified by reverse phase chromatography. The phosphorylated tyrosine was identified as residue 1235 (Tyr1235) by Edman covalent radiosequencing. A synthetic peptide derived from the corresponding MET sequence was phosphorylated by p190MET in an in vitro assay and coeluted in reverse phase chromatography. Tyr1235 lies within the tyrosine kinase domain of p190MET, within a canonical tyrosine autophosphorylation site that shares homology with the corresponding region of the insulin, CSF-1 and platelet-derived growth factor receptors, and of p60src and p130gag-fps. The p190MET kinase is constitutively phosphorylated on tryosine in a gastric carcinoma cell line (GTL16), due to the amplification and overexpression of the MET gene. Metabolic labeling of GTL-16 cells with [32P]orthophosphate followed by immunoprecipitation and tryptic phosphopeptide mapping of p190MET showed that Tyr1235 is a major site of tyrosine phosphorylation in vivo as well. Since phosphorylation activates p190MET kinase, we propose a regulatory role for Tyr1235.
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PMID:Identification of the major autophosphorylation site of the Met/hepatocyte growth factor receptor tyrosine kinase. 165 90

Some human carcinoma cells constitutively produce granulocyte colony-stimulating factor (G-CSF) which stimulates the proliferation and differentiation of the progenitor cells of neutrophilic granulocytes. By introducing mouse G-CSF chromosomal gene or its promoter DNA into human carcinoma cell lines of CHU-2, SK-HEP-1, and U-87MG, it was shown that the constitutive expression of G-CSF in these carcinoma cells was due to the intrinsic activation of nuclear factors which work on the promoter region of the G-CSF gene. A series of 5' deletion mutants, linker scanning mutants, and internal deletion mutants was constructed in the promoter of mouse G-CSF gene and was introduced into human CHU-2 cells to analyze their promoter activities. These studies demonstrated that at least three regulatory elements in the promoter of the G-CSF gene are essential for the constitutive expression of G-CSF in CHU-2 cells. These elements include the consensus decanucleotide "GAGRTTCCA/CC" present on G-CSF, granulocyte/macrophage colony-stimulating factor, and interleukin 3 genes and the "ATTTGCAT" octamer transcription factor binding site. Some point mutations in these consensus sequences significantly diminished the promoter activity in CHU-2 cells.
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PMID:Multiple elements in the promoter of granulocyte colony-stimulating factor gene regulate its constitutive expression in human carcinoma cells. 169 Jul 17

The expression in vivo of FMS transcripts and antigen by neoplastic epithelial cells was demonstrated immunohistochemically or by in situ hybridization in sixteen of seventeen human breast carcinoma specimens and one case of sclerosing adenosis. Expression of CSF-1 receptor (FMS) transcripts and protein was also observed in vitro in two or three breast carcinoma-derived cell lines and was dramatically increased by dexamethasone, a potent glucocorticoid and inducer of mammary epithelial cell differentiation. Immunohistochemical staining with an anti-CSF-1 antibody identified neoplastic epithelial cell co-expression of fms and CSF-1 antigens in more than one-third of the fms-positive invasive carcinoma specimens. These results suggest that autocrine and paracrine interactions of the lymphohematopoietic cytokine CSF-1 and its receptor may participate in the biology of human mammary neoplasms.
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PMID:FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. 182 8

A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, comprising the interleukins 3, 4, and 5, macrophage colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, and the receptor for macrophage-colony-stimulating factor [the CSF1R (formerly FMS) gene product], have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R, which is required for normal proliferation and differentiation of hemopoietic cells of the myeloid lineage. We have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromosome 5, in 10 patients with myelodysplasia and a 5q deletion. We have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R; 6 of 10 were hemizygous and 4 of 10 homozygous for CSF1R loss. The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides. In those patients considered to have homozygous CSF1R loss by DNA experiments the gene was deleted from the 5q chromosome in all cells and from the apparently normal chromosome 5 in a subset of cells. This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromosome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.
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PMID:Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion. 182 36

In this chapter we have described one of the more complex hemopoietic factors, M-CSF. The single-copy M-CSF gene is almost 21 kb in length and is arranged into 10 exons and 9 introns. Expression of the gene at the RNA level is heterogeneous, and several species of M-CSF mRNA have been found in human and murine cells and tissues. In human cells the different mRNAs arise from alternative splicing of the nuclear RNA precursor in both coding and noncoding regions. This results in mRNAs encoding two distinct M-CSF proteins, 256 and 554 amino acids in length. In murine cells only a 552-amino-acid form has been found thus far. All forms of M-CSF have a 32-amino-acid signal peptide and a 23-amino-acid hydrophobic region near the carboxy-terminus, which resembles a transmembrane domain. A large portion of the carboxy-terminal end, including the hydrophobic region, is not found in the mature protein. Thus, the primary translation product of M-CSF is a prepropolypeptide, with processing occurring at both amino- and carboxy-terminal ends. The exact size of the mature protein is still somewhat in doubt, but deletion mutagenesis from the carboxy-terminal end indicates that the protein may be as small as 150 amino acids and still be functional. Site-directed mutagenesis has also shown that the first seven cysteines in the mature molecule are probably necessary for biological activity, whereas the next two cysteine residues are not. In spite of the heavy glycosylation found in the native protein, removal of the N-linked glycosylation signals does not seem to affect activity to any great degree. The M-CSF gene and its receptor, C-FMS, are tightly linked on the long arm of chromosome 5, a unique finding in the ligand/receptor field. This region also contains the genes for GM-CSF, IL-3, ECGF, and the receptor for PDGF. A similar situation may exist on chromosome 11 of the mouse. The close linkage of these factors and receptors is the probable cause for the disorders of hemopoiesis that arise when deletions occur in this area. The preceding discussion has shown how quickly the area of M-CSF molecular biology has advanced in the past 2-3 years. A great deal of effort is now being directed toward expressing M-CSF at high levels in a variety of prokaryotic and eukaryotic systems.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular biology of macrophage colony-stimulating factor. 209 Feb 50

THP-1 is a factor-indepencent, monocytic leukemia cell line which differentiates into adherent macrophages upon treatment with 12-O-tetra-decanoylphorbol-13-acetate (TPA). Unlike its normal counterparts, THP-1 cells display only minimal levels of proto-oncogene c-FMS RNA which encode for membrane M-CSF receptors. Northern blot analysis showed that the c-FMS mRNA levels in THP-1 cells was greatly enhanced during TPA-induced monocytic differentiation. Despite the acquisition of functional activities and induction of c-FMS transcripts after TPA treatment, no surface M-CSF receptors were detected on the THP-1 cells. The inducing activity associated with TPA was completely abrogated when THP-1 cells were pretreated with staurosporine, a potent protein kinase C (PK-C) inhibitor. It is concluded that the activation of the PK-C system is a part of the metabolic cascade essential for the initiation of monocytic differentiation in THP-1 cells.
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PMID:Inhibition of TPA-induced monocytic differentiation in THP-1 human monocytic leukemic cells by staurosporine, a potent protein kinase C inhibitor. 214 May 92


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