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)

Transforming growth factor-beta (TGF-beta) and glial-cell-line-derived neurotrophic factor (GDNF) have been shown to synergize in several paradigms of neuronal survival. We have previously shown that cerebellar granule neurons (CGN) degenerate in low potassium via ERK1/2 (extra-cellular-regulated kinase)-dependent plasma membrane (PM) damage and caspase-3-dependent DNA fragmentation. Here, we have investigated the putative synergistic function of GDNF and TGF-beta in CGN degeneration. GDNF alone prevents low-potassium-induced caspase-3 activation and DNA fragmentation but does not affect either low-potassium-induced ERK activation or PM damage. TGF-beta alone does not affect low-potassium-induced DNA fragmentation but potentiates low-potassium-induced PM damage. This effect of TGF-beta is independent of ERK1/2 activation but dependent on p38-MAPK (mitogen-activated protein kinase) activation. When co-applied with TGF-beta, GDNF paradoxically antagonizes TGF-beta-induced potentiation of PM damage by inhibiting TGF-beta-induced p38-MAPK activation. In addition, PI3K (phosphatidylinositol 3-kinase) inhibitors abolish the GDNF effect. This study thus demonstrates a differential mechanism of action of GDNF and TGF-beta on CGN degeneration. GDNF inhibits caspase-3-dependent DNA fragmentation but does not affect ERK-dependent PM damage. However, GDNF can attenuate TGF-beta-induced p38-MAPK-dependent PM damage via the PI3K pathway.
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PMID:GDNF prevents TGF-beta-induced damage of the plasma membrane in cerebellar granule neurons by suppressing activation of p38-MAPK via the phosphatidylinositol 3-kinase pathway. 1807 53

Disruptions in the expression of the BDNF gene that encodes a neurotrophic factor involved in neuronal survival, differentiation and synaptic plasticity has been proposed to contribute to the molecular pathogenesis of Rett syndrome. Rett syndrome (RTT) is a neurodevelopmental disorder, caused by mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 deficiency in the brain has been shown to decrease overall expression of BDNF in spite of an observed increase in the activity of promoter III that appears to be controlled directly by MeCP2. Therefore, how MeCP2 deficiency causes an overall downregulation of BDNF expression was an enigma. Here we report that MeCP2 deficiency in human and mouse brain causes an increase in expression of two neuronal gene transcriptional repressors REST (RE1 silencing transcription factor), and CoREST. MeCP2 binds to and is involved in repression of Rest and CoRest promoters despite their unmethylated state. MeCP2 depletion is associated with a change in the histone modification profile to a more active conformation. The elevated levels of REST and CoREST in the brain of RTT patients and MeCP2 deficient mice result in downregulation of BDNF, apparently by their binding to the RE1 (element) located between the first two promoters of the BDNF gene. Interestingly, the NTRK2 gene that encodes the BDNF receptor, TRKB, was overexpressed in MeCP2 deficient human and mouse brains either directly or as an attempt to compensate for BDNF deficiency.
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PMID:MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. 1807 16

By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFR alpha 1 (GDNF receptor family alpha-1) are overexpressed in a subset of estrogen receptor-positive tumors. Germ line-activating oncogenic mutations in RET allow this receptor to signal independently of GFR alpha 1 and its ligand glial cell-derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET(+)/GFR alpha 1(+) MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFR alpha 1 receptors.
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PMID:A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. 1808 3

Studies have shown that cytokines released following CNS injury can affect the supportive or cytotoxic functions of microglia. Interleukin-6 (IL-6)-family cytokines are among the injury factors released. To understand how microglia respond to IL-6 family cytokines, we examined the effects of ciliary neurotrophic factor (CNTF) and IL-6 on primary cultures of rat microglia. To assess the functional state of the cells, we assayed the expression of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and cyclooxygenase 2 (COX-2) following stimulation. We show that CNTF reduces COX-2 levels, whereas IL-6 increases the expression of IL-1beta, TNFalpha, and Cox-2. We also examined trophic factor expression and found that CNTF enhances glial cell-line derived neurotrophic factor (GDNF) mRNA and protein secretion, whereas IL-6 has no effect. Correspondingly, conditioned media from CNTF-stimulated microglia promote motor neuron survival threefold beyond controls, whereas IL-6-stimulated microglia decrease neuronal survival twofold. To understand better the signaling mechanisms responsible for the opposite responses of these IL-6-family cytokines, we examined STAT-3 and ERK phosphorylation in CNTF- and IL-6-stimulated microglia. IL-6 markedly increases STAT-3 and ERK phosphorylation after 20 min of treatment, whereas these signal transducers are weakly stimulated by CNTF across a range of doses. We conclude that CNTF modifies microglial activation to support neuronal survival and that IL-6 enhances their capacity to do harm, as a result of different modes of intracellular signaling.
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PMID:Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. 1821 91

Our previous studies have demonstrated the effects of brain derived neurotrophic factor (BDNF) on promoting proliferation of multiple myeloma (MM) cells and inducing angiogenesis in MM in vitro. To further investigate whether the PI3K/Akt and MEK1/ERK pathway play a role in the BDNF-induced angiogenesis in vitro and to explore the further molecular mechanisms, two ways to establish human myeloma xenograft animal model were developed, their advantages and disadvantages were elucidated. The phosphorylation of AKT and ERK1/2 were detected in human umbilical vein endothelial cells (HUVECs) by Western blot. The angiogenic activity in vitro was evaluated by transwell migration assay and tubule formation assay. Cell proliferation was determined by crystal violet staining. Cell apoptosis was detected by FITC-Annexin-V/PI double staining and flow cytometry. The results showed that the BDNF activated the PI3K/Akt and MEK1/ERK pathway in the time-dependent manner. Ly294002 and PD98059 blocked the activation of Akt and ERK1/2 respond to BDNF. 100 ng/ml BDNF significantly increased HUVEC tube formation, migration and proliferation in vitro at a similar degree of 25 ng/ml VEGF. Furthermore, tube formation of HUVECs toward BDNF was significantly inhibited by 57% and 40% with 20 micromol/L Ly294002 and 20 micromol/L PD98059 treatment, respectively. At the same time, Ly294002 and PD98059 reduced the BDNF-induced migration of HUVECs by 74% and 36%, respectively. While BDNF-induced survival was only blocked by Ly294002 and BDNF-induced proliferation was only inhibited by PD98059. It is concluded that BDNF promotes angiogenesis of HUVECs in vitro. ERK and Akt are two crucial events in BDNF-mediated signal transduction leading to HUVECs angiogenesis by different mechanisms. Moreover, the latter is more important.
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PMID:Brain derived neurotrophic factor induces endothelial cells angiogenesis through AKT and ERK1/2 signal pathway. 1831 25

Gastrointestinal stromal tumors (GISTs) comprise a recently defined entity of the most common mesenchymal neoplasms of the gastrointestinal tract. Advances in the understanding of the molecular mechanisms of GIST pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate (inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-alpha) and their downstream signaling cascade) has revolutionized the therapy of advanced (inoperable and/or metastatic) GISTs. Imatinib has now become the standard of care in the treatment of patients with advanced GIST. However, a majority of patients eventually develop clinical resistance to imatinib. Over the last few years major progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the sole approved second-line drug is sunitinib--a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET). However, a number of new generation tyrosine kinase inhibitors, alone or in combination, are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or mammalian target of rapamycin). This article discusses the factors relating to imatinib resistance as well as upcoming potentially effective treatment options for patients with progressive disease available in 2008 and those under investigation with more individualized treatment methods, which has been recently patented. This review focuses on the current achievements in targeted therapy of advanced GISTs, and how the insight into the resistance mechanisms may allow in the near future to treat patients with advanced GISTs.
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PMID:Developments in targeted therapy of advanced gastrointestinal stromal tumors. 1853 51

We used immunohistochemical staining to assess protein over-expression of glial cell-derived neurotrophic factor (GDNF) and its RET receptor tyrosine kinase in patients with pancreatic cancer and benign pancreatic neoplasm, and assessed correlations with clinicopathological features and prognosis. Surgically resected pancreatic cancer patients (40/58, 68.9%) showed positive GDNF immunostaining, a significantly higher frequency than in patients with benign pancreatic tumour (3/11, 27.3%). Intrapancreatic neural invasion by cancer cells was significantly related to over-expression of GDNF. Strongly positive expression of GDNF was significantly more frequent than lesser grades of expression in patients with severe back pain before and 12 months after surgery. Expression of RET was significantly related to lymphatic invasion, survival rate after tumour resection and degree of tumour cell differentiation. We conclude that GDNF may be important in pancreatic cancer proliferation and metastasis, especially in patients with perineural invasion. Strongly positive expression of GDNF may be an indication for early intensified radiotherapy. RET expression in pancreatic cancer tissues may be a useful prognostic marker.
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PMID:The relationship between overexpression of glial cell-derived neurotrophic factor and its RET receptor with progression and prognosis of human pancreatic cancer. 1865 60

Rearranged during transfection, RET, is a receptor tyrosine kinase expressed in neural crest derived cell lineages. RET is activated by dimerisation facilitated by its binding to the heterodimeric complex formed by Glial cell-derived neurotrophic factor (GDNF) -family ligand (GFL) and GNDF-family receptor (GFR). Both GDNFs and their co-receptors are a small protein family of four members. RET kinase mediated signaling can lead to survival, cell growth, differentiation, and migration. Pharmaceutically RET is of interest due to its involvement in several disease conditions. Oncogenic RET activation by mutations or rearragements predisposes to cancers like multiple endocrine neoplasia type 2 (A and B) and medullary thyroid carcinoma. Loss-of-function mutations in RET are a strong susceptibility factor for Hirschsprung disease, which is characterized by lack of ganglion cells in gastrointestinal tract. All the GFLs promote neuronal survival and GDNF is one of the most potent neurotrophic factors for dopaminergic neurons. Therefore, the neuroprotective capacity of RET activation to override the apoptotic program in neurodegenerative diseases, like in dying midbrain dopaminergic neurons in Parkinson's disease, is of great interest. This article reviews the recent international patents on modulation of RET kinase activity by small-molecule and peptide-based agonists and antagonists.
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PMID:Recent inventions on receptor tyrosine kinase RET modulation. 1907 52

Nerve growth factor (NGF) is a well-known neurotrophic factor essential for the survival and maintenance of sensory and sympathetic neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is a genetic disorder due to loss-of-function mutations in the NTRK1 (also known as TRKA) gene encoding TrkA, a receptor tyrosine kinase for NGF. Patients with CIPA provide us a rare opportunity to explore the developmental and physiological function of the NGF-dependent neurons in behavior, cognitive, and mental activities that are not available in animal studies. Here, I discuss the significance of findings that patients with CIPA lack NGF-dependent neurons, including interoceptive polymodal receptors, sympathetic postganglionic neurons, and probably several types of neurons in the brain. They also exhibit characteristic emotional behavior or problems. Together, the NGF-TrkA system is essential for the establishment of a neural network for interoception and homeostasis that may underlie 'gut feelings'. Thus, NGF-dependent neurons play a crucial role in emotional experiences and decision-making processes. Prospective studies focused on these neurons might provide further insights into the neural basis of human emotion and feeling.
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PMID:Nerve growth factor, interoception, and sympathetic neuron: lesson from congenital insensitivity to pain with anhidrosis. 1920 60

Macrophage stimulating protein (MSP) is a pleiotropic growth factor that signals via the RON receptor tyrosine kinase. Here we demonstrate that MSP increases the proportion of cultured adult mouse DRG neurons displaying discernable neuritic processes and promotes the elongation and branching of these processes in a dose dependent manner. RON expression in adult DRG is largely restricted to nerve growth factor (NGF)-responsive nociceptive neurons, and MSP mimics the effects of NGF by increasing the expression of several mRNAs that encode functionally important proteins that are characteristically expressed by this neuronal sub-population. MSP mRNA is expressed at high levels in the peripheral target fields of DRG somatic afferents, but is undetectable in DRG, spinal cord or freshly dissected sciatic nerve. These results suggest that MSP is a peripheral target-derived neurotrophic factor for NGF-responsive adult DRG neurons.
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PMID:Macrophage stimulating protein is a neurotrophic factor for a sub-population of adult nociceptive sensory neurons. 1928 36


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