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)

To assess the expression pattern of basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR-1/flg) during autoimmune inflammation of the CNS, FGF-2, and FGFR1/flg peptide and mRNA levels were examined by immunocytochemistry, by in situ hybridisation and by Northern blot analysis in T cell-mediated EAE of the Lewis rat. In naive control animals as well as in animals injected with non-encephalitogenic, PPD-reactive T lymphocytes, FGF-2 immunoreactivity was low and confined to blood vessels and to a few spinal cord neurons. In rats injected with encephalitogenic, MBP-reactive T lymphocytes, however, FGF-2-immunoreactive cells were detected from day 4 after T cell transfer onward, i.e., from the onset of clinical symptoms. The number of FGF-2 immunoreactive cells was highest between days 6 and 10 after T cell transfer. Increased FGF-2 peptide expression was paralleled by increased FGF-2 mRNA expression on macrophages/microglia in the spinal cord. By 21 days after T cell transfer, i.e. after complete recovery, FGF-2 peptide and mRNA expression had fully subsided. Based on morphological criteria and on double labeling with the macrophage/microglia-binding lectin GSI-B4 two cell types expressed FGF-2: 1) round macrophages within the core, and 2) activated microglia at the edges of white and grey matter perivascular lesions. Paralleling the temporal and spatial expression pattern of FGF-2, FGFR-1/flg immunoreactivity was induced on activated macrophages/microglia but also on reactive astrocytes bordering perivascular inflammatory lesions. In situ hybridisation analysis furthermore showed that macrophages/microglia expressed the FGFR-1/flg mRNA, and that receptor mRNA expression paralleled ligand mRNA expression. Macrophage/microglia-derived FGF-2 could serve two main functions in EAE: 1) regulate microglial activation in an autocrine fashion, and 2) help to target astrocyte-derived insulin-like growth factor-I (IGF-I) to potentially injured oligodendrocytes in demyelination.
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PMID:Differential expression of fibroblast growth factor-2 and receptor by glial cells in experimental autoimmune encephalomyelitis (EAE) 928 Jul 53

Mitomycin C (1) is the prototypical bioreductive alkylating agent. Studies have shown that mitomycin C and its derivatives selectively alkylate guanine residues within di- and trinucleotide DNA sequences. This investigation sought to improve the selective DNA bonding properties of the mitomycins by coupling them with antisense oligodeoxynucleotides. Two procedures were developed that allowed the attachment of a phosphorothioate oligodeoxynucleotide containing a hexylamino spacer at the 5' terminus with a C(10)-activated mitomycin. In the first procedure, decarbamoylation of 1 (NaOCH3/ benzene) afforded 10-decarbamoylmitomycin C (10), which was treated with either dimethyl sulfate or methylthiochloroformate and base to yield 10-decarbamoylporfiromycin (11) and N(1a)-[(methylthio)-carbonyl]-10-decarbamoylmitomycin C (12), respectively. Activation of the C(10) site in 11 and 12 with 1,1'-carbonyldiimidazole or with 1,1'-thiocarbonyldiimidazole provided the N(1a)-substituted mitomycin 10-decarbamoyl-10-O-carbonylimidazoles (5, 7) and 10-decarbamoyl-10-O-thiocarbonylimidazoles (6, 8), respectively. Compounds 5-8 were reacted with glycine methyl ester hydrochloride (17) and base in both methylene chloride and aqueous buffered solutions to determine the ease and efficiency in which these C(10)-activated mitomycin derivatives coupled to amines. It was found that 5-8 all reacted with 17 in methylene chloride to give the coupled products 18-21 but that improved amine coupling yields in water were observed for the 10-decarbamoyl-10-O-thiocarbonylimidazoles 6 and 8 as compared with the 10-decarbamoyl-10-O-carbonylimidazoles 5 and 7. This finding led to the coupling of the phosphorothioate oligodeoxynucleotide, H2N(CH2)6-P(S)(OH)-GGCCCCGTG-GTGGCTCCAT (22) to 8. Compound 22 complemented a 19-base sequence in the translation initiation region of the human A-raf-1 gene. Use of excess 8 (28 equiv) with 22 gave only a 36% yield of the coupled product 23, which proved difficult to separate from 22. In the second procedure, phosphorothioate oligodexynucleotides that contained a hexylamino spacer at the 5'termini were coupled to 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 was prepared in four steps from 11. Mesylation (methanesulfonyl chloride/pyridine) of 11 gave the C(10) mesylate 13, which was then treated with NaN3 (dimethylformamide, 90 degrees C) to give 10-des(carbamoyloxy)-10-azidoporfiromycin (14). Catalytic reduction (PtO2, H2) of 14 in pyridine afforded C(10) amine 15. Treatment of 15 with di-2-pyridyl thionocarbonate provided the desired 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 readily coupled with 17 and base in both methylene chloride and aqueous buffered solutions to give 25. Use of the 5'hexylaminophosphorothioate oligodeoxynucleotides 32-35 in place of 17 gave the conjugated adducts 28-31, respectively, in a 12% to near-quantitative yield. The products were purified by semipreparative HPLC. Antisense agents 28-31 were designed to target a 30-base-long region from the coding region of the human FGFR1 gene. One adduct, 29, reduced the number of FGFR1 receptors in human aortic smooth cells for bFGF on the cell surface, which suggested down-regulation of FGFR1 gene expression. Further, 29 inhibited cultured human aortic smooth muscle cell proliferation and was less cytotoxic than porfiromycin (2). The biological assay data suggest that the phosphorothioate oligodexynucleotide porfiromycin conjugates may be more target selective and less toxic than either mitomycin or porfiromycin and thus be promising therapeutic agents.
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PMID:Design, synthesis, and evaluation of mitomycin-tethered phosphorothioate oligodeoxynucleotides. 895 Apr 85

The FGFs constitute a family of, at least, 12 polypeptides (FGF1 to FGF12) implicated in a number of physiological and pathological processes throughout embryogenesis and adult life. They bind to at least three types of cell surface molecules, including four high affinity transmembrane tyrosine kinase receptors (FGFR1 to FGFR4). In addition to important roles during development, FGF involvement in pathological conditions, including tumour formation, has been suspected, and overexpression of FGFR in tumour specimens is well documented. Diphtheria Toxin/FGF6 (DT/FGF6) mitotoxin has been shown to selectively and effectively target FGFR1-expressing cells. We show here that DT/FGF6 targets myoblasts engineered to express either one of the four FGFR, as well as FGFR-expressing tumour cells.
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PMID:Cytotoxic activity of a diptheria toxin/FGF6 mitotoxin on human tumour cell lines. 901 Feb 26

The comparative biological properties of NBT-II cells, a rat bladder carcinoma cell line constitutively expressing FGF-1 and FGF-2 were analysed in nude mice. FGF-1 is not secreted by the transfected cells unless the cDNA contains a signal sequence; conversely, NBT-II cells transfected with FGF-2 coding sequence produce and secrete the factor in a biologically active form. Bovine brain capillary endothelial cells are stimulated to proliferate upon addition of medium conditioned by the FGF-2-producing cells and this activity can be abrogated by the addition of anti-FGF-2 blocking antibodies. In addition, the FGF-2-containing medium, which cannot stimulate NBT-II cells due to absence of appropriate receptors, is able to induce scattering of NBT-II cells expressing the FGFR1. It has been reported previously that FGF-1-producing cells are highly tumorigenic in nude mice and induce carcinoma with a period of latency reduced from 6 to 5 weeks when compared to parental NBT-II cells. In contrast, NBT-II cells producing FGF-2 are no more tumorigenic than parental cells, indicating that FGF-1 and FGF-2 have different oncogenic properties in carcinoma. FGF-1 and FGF-2 are potent antiogenic factors that trigger the host endothelial cells. VEGF, another potent angiogen was found to be expressed in small amounts by NBT-II cells and to be expressed in reduced amount in the FGF-producing cells. In the NBT-II system in vivo FGF-1 and FGF-2 are highly and comparatively angiogenic in the resultant carcinoma and this occurs in the absence of production of significant amounts of VEGF by the carcinoma cells. Taken together, our results indicate that activated angiogenesis is not sufficient for rapid tumor expansion. FGF-1 behaves as a tumorigenic factor in the NBT-II bladder carcinoma cell model, whereas expression and secretion of large amounts of FGF-2 are not sufficient for increasing tumor growth.
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PMID:FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. 903 74

The present study provides a detailed comparative description in the adult rat brain of areas that express mRNAs coding for the fibroblast growth factor subtype receptors 1-3 (FGFR1-3). One observation in this analysis was a widespread expression in the brain of all three FGFR mRNAs, according to the following rank order: FGFR1, diencephalon < telencephalon < mesencephalon and metencephalon < myelencephalon; FGFR2 and FGFR3, telencephalon < diencephalon < mesencephalon and metencephalon < myelencephalon. Another observation was an apparent cellular specificity in their basal expression. Thus, the FGFR1 mRNA was expressed mainly in large and weakly stained cells, whereas FGFR2 transcripts were expressed primarily in small and strongly stained cells and in cells of brain regions devoid of neuronal cells, such as the white matter. FGFR3 mRNA was always detected in small and strongly stained cells with scattered distribution and was not expressed in the white matter. However, FGFR2 mRNA was weakly expressed also in large cells localized in some nuclei of the lower brainstem, in the diagonal band, and in the septum. Furthermore, in the medial habenula and in the nuclei of the pons, there exists a high density of cells expressing both FGFR1 and FGFR2 (60-100%). With neurotoxic lesions involving 6-hydroxydopamine microinjections in the substantia nigra, reactive glial cells in the lesioned area and surrounding the cannula tract showed an increase in the expression of both FGFR1 and FGFR2 mRNAs, whereas no increased expression was found for FGFR3 mRNA. Taken together, these findings showed that these three FGF receptors exist in all subtypes of cells of each brain region. Their apparent cellular specificity suggests that these receptor subtypes can have a differential trophic role in the brain, reflecting the various biological activities shown by the ligands of the FGF family.
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PMID:Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: in situ hybridization analysis. 905 Jul 87

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.
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PMID:Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. 905 94

To investigate the molecular mechanisms of cholinergic sprouting in the hippocampus after removal of entorhinal cortical inputs, we evaluated trophic factor gene expression in the denervated hippocampus. Despite the proposed role for nerve growth factor (NGF) in this sprouting, we observed no change in NGF mRNA or protein at several postlesion time points. In contrast, FGF-2 mRNA was increased within 16 hr. FGF-2 immunoreactivity was localized within GFAP-positive hypertrophic astrocytes distributed specifically within the denervated outer molecular layer after the lesion. To address the functional significance of this increase in FGF-2, we assessed the magnitude of cholinergic sprouting in animals receiving chronic intracerebroventricular infusions of neutralizing antibodies specific for FGF-2 and compared it with that observed in lesioned animals receiving infusate controls. Animals given FGF-2 antibodies displayed a marked reduction in cholinergic sprouting as compared with controls. In fact, many of these animals exhibited virtually no sprouting at all despite histological verification of complete lesions. These results suggest that endogenous FGF-2 promotes cholinergic axonal sprouting in the injured adult brain. Furthermore, immunocytochemical localization of receptors for FGF-2 (i.e., FGFR1) on projecting basal forebrain cholinergic neurons suggests that FGF-2 acts directly on these neurons to induce the lesion-induced sprouting response.
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PMID:Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. 906 10

A primary culture system of olfactory cells derived from newborn mouse was established by coculturing with a feeder layer of brain astrocytes. In this system, the whole lifespan of olfactory cells could be observed in vitro. Neurogenesis occurred from 5 days after plating and coexistence of immature and mature olfactory cells was observed until day 14. After day 15, immature cells were diminished and most of the culture cells appeared differentiated after day 20. The lifespan of differentiated cells was estimated to be 3 to 6 weeks. Cultured cells expressed growth associated protein 43 (GAP43), neurofilament protein (NFP), protein gene product 9.5 (PGP9.5) and olfactory marker protein (OMP). In addition, other round cells were cytokeratin-positive by immunostaining. RT-PCR of growth factor receptors on the coculture cells revealed the expressions of fibroblast growth factor receptor 2 (FGFR2) and FGFR3, both of which could not be detected in the feeder cell layer of astrocytes. FGFR1 and transforming growth factor beta receptor (TGF beta R) were detected both on the coculture and on feeder cells. FGFR4, insulin-like growth factor 2 receptor (IGF2R) and hepatocyte growth factor receptor (HGFR) could not be detected in both samples. Furthermore, basic FGF, a prototypic FGF, was also found in the coculture system and in feeder cells. The present study indicated FGF might affect regulation of proliferation and differentiation of olfactory cells.
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PMID:[Proliferation and differentiation of olfactory cells in primary culture system]. 910 46

Hydrogen peroxide stimulated tyrosine phosphorylation of several proteins in growth-arrested vascular smooth muscle cells (VSMC). One of these proteins was identified as fibroblast growth factor receptor type I (FGFR1). In addition, induced tyrosine phosphorylation of FGFR1 by hydrogen peroxide resulted in complex formation with Grb2. Hydrogen peroxide also caused a time-dependent activation of extracellular signal-regulated protein kinases (ERKs; p42&p44) group of mitogen-activated protein kinases (MAPKs) in VSMC. The time courses of the hydrogen peroxide-stimulated FGFR1 tyrosine phosphorylation and ERKs activation were followed by induced expression of c-fos and c-jun. Genistein, a potent inhibitor of protein tyrosine kinases, significantly blunted the hydrogen peroxide-induced FGFR1 tyrosine phosphorylation, ERKs activation and c-fos and c-jun expression. PD98059, a specific inhibitor of MEK1, attenuated the hydrogen peroxide-induced ERKs activation and c-fos and c-jun expression. Together, these results suggest that oxidants such as hydrogen peroxide stimulate tyrosine phosphorylation of receptor tyrosine kinases and these, in turn, mediate the down-stream signalling events including the recruitment of Grb2 by the receptor, activation of ERKs and induction of c-fos and c-jun expression.
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PMID:Protein tyrosine kinase activity is required for oxidant-induced extracellular signal-regulated protein kinase activation and c-fos and c-jun expression. 911 18

Fibroblast growth factor receptor 3 (FGFR3) is a developmentally regulated transmembrane protein. Three other FGFRs (1, 2, and 4) in conjunction with FGFR3 are part of the receptor tyrosine kinase super-family. Mutations in three of these genes (FGFR1, 2, and 3) have been determined to be the cause of human growth and developmental disorders. We have characterized a 22-kb DNA fragment containing the human FGFR3 gene and determined 11 kb of its nucleotide sequence. The gene consists of 19 exons and 18 introns spanning 16.5 kb, and the boundaries between exons and introns follow the GT/AG rule. The translation initiation and termination sites are located in exon 2 and exon 19 respectively. The sequence of the 5'-flanking region (1.5 kb) lacks the typical TATA or CAAT boxes. However, several putative binding sites for transcription factors SP1, AP2, Krox 24, IgHC.4, and Zeste are present. The 0.77-kb region from position -889 (5'-flanking region) to -119 (intron 1) contains a CpG island. A comparative sequence analysis of the human and mouse FGFR3 genes indicates that the overall genomic structure and organization of the human gene are nearly identical to those of its mouse counterpart. Furthermore, there is a striking similarity in the promoter regions of both genes, and several of the putative transcription factor-binding sites are conserved across species, suggesting a definitive role of these factors in the transcriptional regulation of these genes.
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PMID:Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Fgfr3 gene. 912 76


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