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)

Previous studies from this laboratory have characterized RAW117-P murine large cell B-cell lymphoma and its in vivo selected highly malignant and liver metastatic RAW117-H10 subline for their biological and biochemical properties. In this study, to understand the molecular basis of low and high metastatic behavior of these variant sublines, we have investigated the molecular phenotypes of these cells using differential display techniques and cDNA array analysis. Differential display analysis indicated a significant difference in expression of several genes between these two metastatic variant lymphoma cells. Further analyses of these cells using microarray showed an increased expression of several genes including uPAR1, CRE-BP1, Chop-10, IGF, insulin-like growth factor-IA, STAT6, Cyclin-D1, Cyclin-E, ERBB-3, Alpha NGF, Kruppel-like factor LKLF, (P)19INK4 in metastatic RAW117-H10 cells compared to parental RAW117-P cells. On the other hand, MIP1beta, CD14 antigen, Cathepsin B and MOD are expressed more in RAW117-P cells compared to RAW117-H10 cells. Differential expression of the selected genes was confirmed using semiquantitative RT-PCR techniques. The combination of plasminogen activator and its receptor and IGF-like growth factors, cell cycle regulatory molecules and transcription factors might provide an ideal environment for RAW117-H10 cells to metastasize to distant organs and colonize. Thus these results identify certain differentially expressed genes that are involved in the metastatic properties of these lymphoma cells and lay foundation for further in depth analyses to use this information to develop therapy for metastatic lymphoma.
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PMID:Differential gene expression in murine large cell B-cell lymphoma metastatic variants. 1860 72

The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4-saporin, a selective toxin for IB4+/Ret+-nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFRa1/Ret: PLCc, CDK5, PI3K,MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype.
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PMID:GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. 1861 64

We observed that recombinant ciliary neurotrophic factor (CNTF) enhanced survival and neurite outgrowth of cultured adult rat dorsal root ganglion (DRG) neurons. Among other neurotrophic factors (NGF and GDNF) and interleukin (IL)-6 cytokine members [IL-6, LIF, cardiotrophin-1, and oncostatin M (OSM)] at the same concentration (50 ng/ml), CNTF, as well as LIF and OSM, displayed high efficacy for the promotion of the number of viable neurons and neurite-bearing cells. CNTF enhanced the number of neurite-bearing cells in both small neurons (soma diameter <30 microm) and large neurons (soma diameter > or =30 microm), whereas NGF and GDNF promoted that in only small neurons. Western blot analysis revealed that CNTF induced phosphorylation of STAT3, Akt, and ERK1/2 in the neurons. Furthermore, the neurite outgrowth-promoting activity of CNTF was diminished by co-treatment with Janus kinase (JAK) 2 inhibitor, AG490; STAT3 inhibitor, STA-21; phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor, LY294002; and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, in a concentration-dependent manner. Its survival-promoting activity was also affected by AG490, STA-21, and LY294002 at higher concentrations, but not by PD98059. These findings suggest the involvement of JAK2/STAT3, PI3K/Akt, and MEK/ERK signaling pathways in CNTF-induced neurite outgrowth, where the former two pathways are thought to play major roles in mediating the survival response of neurons to CNTF.
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PMID:Neuroprotective properties of ciliary neurotrophic factor for cultured adult rat dorsal root ganglion neurons. 1867 4

Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase-polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB(+) cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target.
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PMID:High-affinity neurotrophin receptors and ligands promote leukemogenesis. 1905 81

Recognition of the molecular events that lead to enhanced cell death is vital to understand the developmental cerebellar defects under hypothyroidism. Though neurotrophins promote the survival and development of neurons in the cerebellum, but the mechanism of their insufficiency mediated cell loss under hypothyroidism is unknown. Here in developmental hypothyroid rat model we report that hypothyroidism induced neuronal loss involve down regulation of neurotrophic survival signaling and increased truncation of the receptor p75(NTR). Results showed that perinatal hypothyroidism besides repressing the expression of BDNF also impairs the maturation of NGF which results in decreased activation of ERK, CREB, NF-kappaB and AKT. Furthermore hypothyroidism caused an enhanced expression and proteolysis of p75(NTR). The increased proteolysis of p75(NTR)in vivo and its association with death of granule neurons brings forward hitherto a p75(NTR) dependence signaling which along with compromised survival signaling could provide a neurotrophic basis of understanding the cause of enhanced cell death in developing cerebellum under hypothyroidism.
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PMID:Enhanced neuronal loss under perinatal hypothyroidism involves impaired neurotrophic signaling and increased proteolysis of p75(NTR). 1913 44

Differential labelling techniques like differential in-gel electrophoresis (DIGE) enable mixing a control with an experimental sample prior to protein separation, thereby reducing complexity and greatly improving the resolution and analysis of changes in protein expression. Although the shift caused by phosphorylation to a more acidic pI can, in principle, reveal phosphorylation events using DIGE, analysis and verification of the phosphorylation are fraught with problems. Here we describe a differential phospho-labelling technique that obtains the same advantages as DIGE, which we named DIPPL, for differential phosphoprotein labelling. The technique involves labelling two samples, one with 32Pi (orthophosphate) and the other with 33Pi (orthophosphate). The two samples are mixed and proteins are separated on a single gel. Dried gels are exposed twice: once so that total radiation from 32P and 33P is collected on a film or screen; then acetate sheets are interposed between the gel and the screen such that 33P radiation is filtered out leaving 32P radiation to filter through. We demonstrate the utility of this approach by studying the MEK/ERK-dependent changes in stathmin phosphorylation induced by NGF in primary sympathetic neurons.
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PMID:Differential phosphoprotein labelling (DIPPL) using 32P and 33P. 1924 Oct 2

Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.
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PMID:Trk receptor expression and inhibition in neuroblastomas. 1941 27

Compounds isolated from Magnolia officinalis such as magnolol, honokiol and obovatol exhibit several pharmacological effects on CNS including depressant, anxiolytic and anticonvulsant effects, as well as neuroprotective effects against chemical and heat damages. Recently, honokiol was found to have a neurotrophic effect in fetal rat cortical neurons. In the present study, we show that 4-O-methylhonokiol, a novel compound from Magnolia officinalis, promotes neurite outgrowth in a concentration- dependent manner in rat embryonic neuronal cells. In parallel with the neurite outgrowth activity, the expression of neurite outgrowth marker proteins is also increased by treatment with 4-O-methylhonokiol. We also found that 4-O-methylhonokiol promotes the release of NGF and BDNF into cell culture medium. In addition, lower concentration of 4-O-methylhonokiol (1 and 2 lM) further enhanced neurite outgrowth and expression of neurite outgrowth marker proteins in the presence of NGF (50 ng/ml) or BDNF (10 ng/ml). Subsequently, we found that 4-O-methylhonokiol activates ERK in a concentration- dependent manner. However, the neurite outgrowth activity and the NGF and BDNF release induced by 4-O-methylhonokiol are suppressed by an ERK-specific inhibitor. These results suggest that 4-O-methylhonokiol has the ability to induce neurite outgrowth via the increase of neurotrophic factor levels through ERK activation.
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PMID:Neurite outgrowth effect of 4-O-methylhonokiol by induction of neurotrophic factors through ERK activation. 1955 13

Reduced retrograde transport of neurotrophins (NT) and their receptors has been hypothesized to contribute directly to retinal ganglion cell (RGC) loss in glaucoma. However, strategies of supplementing NT and NT receptors have failed to avert ultimate RGC death in experimental glaucoma. This study examines the response of major components of the NT system and their interacting proteins in a rat glaucoma model. Unilateral chronic intraocular pressure (IOP) elevation was produced by episcleral vein injection of hypertonic saline (N = 99). Retinas were collected and grouped by extent of optic nerve injury. Quantitative reverse transcription PCR, western blot analysis and immunohistochemistry were used to determine mRNA and protein levels and protein localization. Out of three RGC-specific Brn3 proteins (Brn3a, b, and c), only Brn3a was significantly downregulated at the message level to 35 +/- 4% of fellow values with the severest nerve injury. With IOP elevation, no significant alterations were found in retinal mRNA levels for BDNF, NGF, NT-4/5 or NT-3. The abundance of mature retinal BDNF protein was not significantly affected by elevated IOP, while proBDNF protein decreased linearly with increasing injury grade (r(2) = 0.50). In retinas with the severest nerve injury, TrkB and TrkC receptor mRNA levels significantly declined to 67 +/- 9% and 44 +/- 5% of fellow values, respectively. However, the levels of TRKB protein and its phosphorylated form were unchanged. Message level for p75(NTR) was linearly upregulated up to 219 +/- 26% with increasing injury (r(2) = 0.46), but no alteration was detected at protein level. The mRNA expression of p75(NTR) apoptosis adaptor proteins NADE, NRIF, and Lingo1 were significantly downregulated in retinas with the greatest nerve injury. A positive correlation was found between injury extent and message levels for Jun (r(2) = 0.23) as well as Junb (r(2) = 0.27), and RGC labeling of activated JUN protein increased. Atf3 mRNA levels demonstrated a positive linear correlation to the extent of injury (r(2) = 0.53), resulting in a nearly five-fold increase (482 +/- 76%) in eyes with the greatest nerve damage. Among downstream pro-survival signaling components, Erk5 mRNA expression was linearly upregulated (r(2) = 0.32) up to 157 +/- 15% of fellow values in retinas with the severest nerve injury (p < 0.01). A slight positive correlation was found between NF-kappaB message levels and injury extent (r(2) = 0.12). Bcl-xl mRNA levels in the most severely injured retinas were significantly reduced to 83 +/- 7% by elevated IOP exposure. Message levels for Erk1/2, Akt1-3 or Bcl2 appeared unaffected. Elevated IOP did not alter mRNA levels of pro-apoptotic Bim, Bax, or p53. This study demonstrates that elevated IOP exposure does not result in a dramatic decrease in retinal levels of either BDNF or its receptor, TrkB. It shows that the responses of NT pathways to elevated IOP are complex, particularly with regard to the role of p75(NTR) and Atf3. A better understanding of the roles of these proteins in IOP-induced injury is likely to suggest informed strategies for neuroprotection in glaucoma.
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PMID:Does elevated intraocular pressure reduce retinal TRKB-mediated survival signaling in experimental glaucoma? 1968 84

NRAGE, also denominated as MAGE-D1 or Dlxin-1, is firstly identified as a molecule interacting with NGF low affinity receptor p75NTR. It facilitates cell cycle arrest and NGF-dependent neuronal apoptosis. Here we report that NRAGE is downregulated while p75NTR is upregulated during the process of NGF-induced neuronal differentiation of PC12 cells. Knockdown of NRAGE by RNA interference accelerates NGF-mediated neurite outgrowth. In addition, in the NRAGE-suppressed cells, NGF-induced ERK activation is increased and this activation is MEK-dependent. Conversely, NRAGE overexpression significantly represses NGF-induced ERK activation. Further studies revealed that NRAGE downregulates TrkA expression through a post-transcriptional manner and thereby blocks NGF-induced TrkA phosphrylation at tyrosine-490. Altogether, these data indicate for the first time that NRAGE is an endogenous inhibitor for NGF-induced neuronal differentiation of PC12 cells by regulating TrkA-ERK signaling.
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PMID:NRAGE is a negative regulator of nerve growth factor-stimulated neurite outgrowth in PC12 cells mediated through TrkA-ERK signaling. 2012 20


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