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)

Adherent cultures of E10.5 rat neuroepithelial cells (NEP cells) from the caudal neural tube require FGF (fibroblast growth factor) and CEE (chick embryo extract) to proliferate and maintain an undifferentiated phenotype in culture. Epidermal growth factor (EGF) does not support E10.5 NEP cells in adherent culture and NEP cells do not form EGF-dependent neurospheres. NEP cells, however, can be grown as FGF-dependent neurospheres. NEP cells express nestin and lack all lineage-specific markers for neuronal and glial sublineages, retain their pleuripotent character over multiple passages, and can differentiate into neurons, astrocytes, and oligodendrocytes when plated on laminin in the absence of CEE. In clonal culture, NEP cells undergo self-renewal and generate colonies that vary in size from single cells to several thousand cells. With the exception of a few single-cell clones, all other NEP-derived clones contain more than one identified phenotype, with over 40% of the colonies containing A2B5, beta-111 tubulin, and GFAP-immunoreactive cells. Thus, NEP cells are multipotent and capable of generating multiple neural derivatives. NEP cells also differentiate into motoneurons immunoreactive for choline acetyl transferase (ChAT) and the low-affinity neurotrophin receptor (p75) in both mass and clonal culture. Double labeling of clones for ChAT and glial, neuronal, or oligodendrocytic lineage markers shows that motoneurons always arose in mixed cultures with other differentiated cells. Thus, NEP cells represent a common progenitor for motoneurons and other spinal cord cells. The relationship of NEP cells with other neural stem cells is discussed.
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PMID:Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis. 920 40

Receptor tyrosine kinase RYK is a mammalian homologue of Drosophila Lio, which is involved in learning and memory and in axon guidance. We cloned a rat ryk gene and characterized its expression pattern in the central nervous system. Northern blot analysis of the whole brain revealed that the RYK mRNA was abundant during the period from 13 to 18 embryonic days (E13-18) and it decreased by E20. In the postnatal brain, the RYK signal was higher in postnatal one week (P1W) cerebrum and in P2W cerebellum than in later stages. In situ hybridization revealed that RYK was expressed throughout the central nervous system, mainly in the ventricular zone on E11 and E13. On E18 and E20, the remarkable level of RYK mRNA was detected in the ventricular zone as well as in the cortical plate of the forebrain. These two regions overlapped the immunoreactive areas of nestin and MAP2, a neural stem cell marker and a mature neural marker, respectively. Moreover, the double-labeling analysis showed that the same cells expressed both RYK and nestin in the ventricular zone. In the postnatal brain, RYK was predominantly expressed in neurons of various regions. These observations suggest that RYK plays a contributory role as a multifunctional molecule in the differentiation and maturation of neuronal cells in the central nervous system.
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PMID:Expression of receptor tyrosine kinase RYK in developing rat central nervous system. 1020 53

Dramatic progress has been made over recent years toward the elucidation of the mechanisms regulating lineage determination and cell survival in the developing peripheral nervous system. However, our understanding of Schwann cell development is limited. This is partly due to the difficulties in culturing primary Schwann cell precursor cells, the earliest developmental stage of the Schwann cell lineage defined to date. Both the inability to maintain cultured Schwann cell precursor cells in an undifferentiated state and the technical difficulties involved in their isolation have hampered progress. We have conditionally immortalized rat Schwann cell precursor cells using a retrovirally encoded EGFR/neu fusion protein to circumvent these problems and to generate a source of homogeneous cells. The resulting SpL201 cell line expresses p75 and nestin, two proteins expressed by neural crest-derived cells, as well as peripheral myelin protein 22, protein zero, and Oct-6 as markers of the Schwann cell lineage. When cultured in EGF-containing medium, the SpL201 cells proliferate and maintain an undifferentiated, Schwann cell precursor cell-like state. The cell line is dependent on EGF for survival but can differentiate into early Schwann cell-like cells in response to exogenous factors. Like primary rat Schwann cells, SpL201 cells upregulate Oct-6 and myelin gene expression in response to forskolin treatment. Furthermore, the SpL201 cell line can form myelin in the presence of axons in vitro and is capable of extensively remyelinating a CNS white matter lesion in vivo. Thus, this cell line provides a valuable and unique tool to study the Schwann cell lineage, including differentiation from the Schwann cell precursor cell stage through to myelination.
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PMID:SpL201: a conditionally immortalized Schwann cell precursor line that generates myelin. 1157 82

In the present study, we investigated the effect of glucocorticoid on neuronal differentiation of hippocampal progenitor HiB5 cells. Dexamethasone (DEX), a synthetic glucocorticoid, inhibited platelet-derived growth factor (PDGF)-induced differentiation of HiB5 cells. The inhibitory effect of DEX was antagonized by RU486, a glucocorticoid receptor (GR) antagonist, indicating the GR-mediated processes. Nestin mRNA level was decreased and midsize neurofilament (NF-M) mRNA level was increased as a function of neuronal differentiation. DEX significantly blocked PDGF-induced down-regulation of nestin mRNA level, and up-regulation of NF-M mRNA level, which were similar to those of undifferentiated cells. DEX inhibited PDGF-induced activation of cyclic AMP-responsive element binding protein (CREB) and AP-1, suggesting that glucocorticoid interfered with signal transduction cascades linking the PDGF receptor and downstream transcription factors. Indeed, DEX reduced PDGF-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Tyrosine phosphatase inhibitor reversed the effect of DEX on ERK1/2. In accordance with this finding, blockage of ERK1/2 signaling pathway with PD098059, a potent inhibitor for Ras/ERK pathway, mimicked the inhibitory effect of DEX on differentiation processes. Taken together, these results indicate that glucocorticoid inhibits PDGF-induced differentiation of hippocampal progenitor HiB5 cells by inhibiting the ERK1/2 signaling cascade via a tyrosine phosphatase-dependent mechanism.
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PMID:Glucocorticoid inhibits growth factor-induced differentiation of hippocampal progenitor HiB5 cells. 1173 13

Hair cell (HC) and supporting cell (SC) productions are completed during early embryonic development of the mammalian cochlea. This study shows that acutely dissociated cells from the newborn rat organ of Corti, developed into so-called otospheres consisting of 98% nestin (+) cells when plated on a non-adherent substratum in the presence of either epidermal growth factor (EGF) or fibroblast growth factor (FGF2). Within cultured otospheres, nestin (+) cells were shown to express EGF receptor (EGFR) and FGFR2 and rapidly give rise to newly formed myosin VIIA (+) HCs and p27(KIP1) (+) SCs. Myosin VIIA (+) HCs had incorporated bromodeoxyuridine (BrdU) demonstrating that they were generated by a mitotic process. Ultrastructural studies confirmed that HCs had differentiated within the otosphere, as defined by the presence of both cuticular plates and stereocilia. This work raises the hypothesis that nestin (+) cells might be a source of newly generated HCs and SCs in the injured postnatal organ of Corti.
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PMID:Proliferative generation of mammalian auditory hair cells in culture. 1185 Jan 80

The KIT-positive specific gastrointestinal stromal tumors (GISTs), leiomyomas, and schwannomas are the three most common types of primary mesenchymal tumors of the gastrointestinal (GI) tract. The intermediate filaments are abundant cytoskeletal proteins commonly used as cell differentiation markers in diagnostic immunohistochemistry. Their patterns have not been fully characterized in GI mesenchymal tumors, and could offer differential diagnostically useful parameters. Very recently, nestin, a class VI intermediate filament expressed in neuroectodermal stem cells and skeletal muscle progenitor cells, has been shown in GISTs and suggested as a marker for these tumors. In this study we immunohistochemically examined the expression of nestin and other intermediate filament proteins, including desmin, keratins (Ks), glial fibrillary acidic protein (GFAP), neurofilament, and vimentin in GISTs of different sites, esophageal leiomyomas and GI schwannomas. Nestin was nearly consistently present in GISTs of different locations whether spindle cell or epithelioid, and benign or malignant. It was also detected in 23 of 24 (96%) GI schwannomas, whereas leiomyomas were uniformly negative. Vimentin was present in both GISTs and schwannomas, whereas it was typically absent in leiomyomas (25% positive, usually focally). Desmin was present in all leiomyomas, whereas only 3% of GISTs (4 of 140) were positive, and all schwannomas were negative. K18 was detected in a minority of GISTs, leiomyomas, and schwannomas. Malignant GISTs were more commonly keratin positive than the benign ones; there was 18% K18 positivity in malignant gastric and small intestinal GISTs, but 9% K18 positivity in benign gastric and small intestinal GISTs. Moreover, K8, albeit to a lesser degree, was detected in a minority of GISTs, but K7, K14, K19 and K20 were not detected. GFAP was present in the majority of schwannomas, whereas all GISTs were negative; some leiomyomas had weak cytoplasmic positivity. These results document distinctive patterns of intermediate filament proteins in GI mesenchymal tumors. Nestin is confirmed to be consistently expressed in GISTs but it is also present in most GI schwannomas; GFAP is helpful when separating GISTs and schwannomas, since only the latter are positive. The potential presence of K8 and K18 in GISTs should not lead to the misdiagnosis of carcinoma on biopsy.
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PMID:Patterns of nestin and other intermediate filament expression distinguish between gastrointestinal stromal tumors, leiomyomas and schwannomas. 1219 11

The mammalian RYK is an orphan receptor that contains a catalytically inactive tyrosine-kinase-related domain. Its Drosophila homolog, Lio/Drl, is required for axon pathfinding in developing brain. Our previous study suggested that RYK mRNA is expressed in nestin-positive progenitor cells and neurons. In the present study, immunohistochemistry has been used to further localize RYK in the central nervous system of rats to identify the lineage of the RYK-expressing cells. In the embryonic forebrain, RYK colocalized with nestin in the ventricular zone and with MAP2 in the cortical plate, suggesting that RYK is expressed in neural progenitor cells and neurons. Localization of RYK in embryonic spinal cord also suggested its expression in both cell types. In primary cultures of rat cerebrum, RYK expression was observed in all neurons, as well as in a significant population of oligodendrocytes, O-2A progenitor cells, and type-2 astrocytes. However, no RYK expression was detected in type-1 astrocytes or microglia. Multipotent neural stem cell line MNS-70 was also analyzed for expression of RYK, and most of the cells were positive for both RYK and nestin in the undifferentiated stage. In the differentiated stage, expression of RYK was detected in the neurons, but not in type-1 astrocytes. In conclusion, RYK is expressed in nestin-positive progenitor cells and neurons, and in a certain population of oligodendrocytes, O-2A progenitor cells, and type-2 astrocytes in developing CNS. These findings show that expression of RYK in rat CNS is tightly regulated in a cell-type-specific manner.
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PMID:Cell-type-specific expression of protein tyrosine kinase-related receptor RYK in the central nervous system of the rat. 1222 82

Gastrointestinal stromal tumor (GIST) is now defined as a specific, KIT-expressing and KIT-signaling driven mesenchymal tumor of the gastrointestinal (GI) tract. The specific identification of GIST has become more important after the availability of KIT-selective tyrosine kinase inhibitor Imatinib mesylate, STI571, commercially known as Gleevec/Glivec (Novartis Pharma, Basel, Switzerland) in the treatment of unresectable and metastatic tumors. GISTs are the most common mesenchymal neoplasms of the GI tract, and encompass most tumors previously classified as gastric and intestinal smooth muscle tumors. GISTs typically present in adults over 40 years (median age 55-60 years) and only exceptionally in children. They can present anywhere in the GI-tract from the lower esophagus to the anus. A great majority of GISTs occur in the stomach (60-70%) or small intestine (25-35%). Colon, rectum, appendix (together 5%) and esophagus (2-3%) are rare sites. Some GISTs are primary in the omentum, mesentery or retroperitoneum, unrelated to the tubular GI-tract, but most GISTs in these sites are metastases from gastric or intestinal primary. Histologically GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones, and morphology differs somewhat by site. By definition, GISTs are KIT(CD117)-positive. Positivity for nestin (90-100%) and CD34 (70%) are also characteristic but less specific features. Smooth muscle actins (20-30%) and heavy caldesmon (80%) are often expressed, whereas desmin is usually absent. Predictive of malignancy are mitotic rate over 5 per 50 HPF or size over 5 cm. However, mitotically inactive intestinal tumors can metastasize, and gastric tumors are in average less often malignant than the intestinal ones. True smooth muscle tumors, GI-schwannoma and undifferentiated sarcomas are the most important differential diagnoses. KIT activating mutations occur in 70-80% of cases. Their signaling consequences, clinical correlation and response to tyrosine kinase inhibitors, and specific genetic alterations are under intense investigation. Majority of these mutations are in-frame-deletions and missense mutations clustering in the 5'-end of juxtamembrane domain (exon 11). A rare mutation, an Ala502-Tyr503 duplication in exon 9, is specific for intestinal GISTs.
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PMID:Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. 1281 76

Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.
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PMID:Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. 1526 71

Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5' upstream promoter (5'UP) gave the highest activity, followed by 5'UP, and the second intron plus 5'UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.
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PMID:Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. 1550 61


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