Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP response element-binding protein (CREB) plays important roles in neuronal plasticity and amyloid beta-peptide (Abeta)-induced cognitive impairment in Alzheimer's disease (AD). Here we demonstrated that Ginkgo biloba extract, EGb 761, displayed the neuron protective effect by activating the CREB signaling pathway. Wild-type neuroblastoma cells cultured in a conditioned medium containing cell-secreted Alphabeta exhibited reduced levels of phosphorylated CREB (pCREB). Addition of EGb 761 (100 microg/mL) or an anti-oligomer-specific antibody (A-11) to the conditioned medium could restore pCREB level. In a neuroblastoma cell line expressing Alphabeta, treatment with EGb 761 increased levels of pCREB and brain-derived neurotrophic factor. Furthermore, CREB phosphorylation induced by EGb 761 was blocked by inhibitors of several upstream signaling pathways of CREB, including protein kinase C, ERK, ribosomal S6 kinase(RSK)90 and nitric oxide pathway. Moreover, these inhibitors differentially blocked the effects of individual components of EGb 761, ginkgolide C, quercetin and bilobalide, which suggest diverse effects of the EGb 761 individual components. Actions of individual EGb 761 components provide further insights into direct mechanisms underlying the effect of EGb 761 on enhancing the cognitive performance of patients with AD.
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PMID:Restoration of impaired phosphorylation of cyclic AMP response element-binding protein (CREB) by EGb 761 and its constituents in Abeta-expressing neuroblastoma cells. 1800 Dec 88

Germ line gain-of-function mutations in several members of the RAS/ERK pathway, including PTPN11, KRAS, and RAF1, cause the autosomal dominant genetic disorder Noonan Syndrome (NS). NS patients are at increased risk of leukemia/myeloproliferative disease and possibly some solid tumors, such as neuroblastoma. Recently, SOS1 gain of function mutations have also been shown to cause NS. Somatic PTPN11, KRAS, and RAF1 mutations occur (although at different frequencies) in a variety of sporadic neoplasms, but whether SOS1 mutations are associated with human cancer has not been evaluated. We sequenced DNA from a total of 810 primary malignancies, including pancreatic, lung, breast, and colon carcinomas, and acute myelogenous leukemia, as well as several neuroblastoma cell lines. From this large, diverse series, missense SOS1 mutations were identified in a single pancreatic tumor, one lung adenocarcinoma, and a T-cell acute lymphoblastic leukemia cell line. Our findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer.
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PMID:SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. 1806 48

The fungal alkaloid militarinone A (MiliA) was recently found to stimulate neuronal outgrowth in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways. Application of equal concentrations of MiliA to other cells such as the murine neuroblastoma cell line N2a resulted in immediate onset of apoptosis by nuclear translocation of apoptosis inducing factor (AIF), activation of caspases and c-Jun/AP-1 transcription factor without an intermediate differentiated phenotype, although minor transient phosphorylation of PKB and MAPK as well as activation of NF-kappaB were also observed. Translocation of AIF was preceded by p53 phosphorylation at Ser15 and blocked by pifithrin alpha, a known inhibitor of p53-transcriptional activity. We here show that both cell types activate the same pathways albeit in different time scales. This is mainly due to contrasting basal expression levels of p53, which in turn regulates expression of AIF. In PC-12 cells, continuous activation of these pathways after prolonged treatment with 40 muM MiliA first led to up-regulation of p53, phosphorylation of p53, release of AIF from mitochondria and its translocation into the nucleus. Additionally, also activation of the c-Jun/AP-1 transcription factor was observed, and PC-12 cells subsequently underwent apoptosis 48-72 h post-treatment. We report that similar pathways working on different levels are able to initially shape very divergent cellular responses.
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PMID:Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53. 1829 87

Endothelins (ETs), which were originally found to be potent vasoactive transmitters, were known to be implicated in nervous system, but the mode of mechanism remains unclear. ETs (ET-1, ET-2, and ET-3) were added to HN33 (mouse hippocampal neuron chi neuroblastoma) cells. Among the three types of ET, only ET-1 increased the intracellular calcium levels in a PLC dependent manner with the induction of ERK 1/2 activation. As the result of ET-1 exposure, the survival rate of HN33 cells and the PKCalpha translocation into the plasma membrane were increased. We suggest that ET-1 participated in the neuroprotective effect involving the calcium-PKCalpha-ERK1/2 pathway.
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PMID:Endothelin 1 protects HN33 cells from serum deprivation-induced neuronal apoptosis through Ca(2+)-PKCalpha-ERK pathway. 1830 2

Biosynthesis of TRH, a neuropeptide involved in energy homeostasis, is modulated by glucocorticoids. TRH mRNA and peptide levels are increased upon incubation of hypothalamic cells with dexamethasone or with cAMP analogs but when combined, a mutual antagonism is observed. These effects are observed at the transcriptional level and on binding of glucocorticoid receptor (GR) or pCREB to the composite GRE (cGRE) and CRE-2 sites of TRH promoter. The present work studied the involvement of PKC and MAPK pathways on the effect of dexamethasone and on its interaction with cAMP signaling in hypothalamic cell cultures. PKC or MEK inhibition abolished dexamethasone-stimulatory effect on TRH mRNA levels, as well as its interference with the stimulatory effect of 8Br-cAMP. Binding of nuclear extracts from hypothalamic or neuroblastoma cells stimulated with dexamethasone or 8Br-cAMP to oligonucleotides containing the CRE or cGRE sites of TRH gene promoter was decreased if cells were preincubated with PKC or MEK inhibitors. Mutations on the AP-1 or the GRE half sites of cGRE showed that GR binds as an heterodimer on cGRE, and PKC or MEK inhibitors diminish binding at the AP-1 site. PKC and ERK signaling thus modulate GR activity and its interaction with CREB or AP-1 at the TRH gene promoter.
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PMID:The PKC and ERK/MAPK pathways regulate glucocorticoid action on TRH transcription. 1842 88

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated. In this study, we report that phosphorylation of cyclic AMP response element binding protein (CREB) is enhanced in both a neuroblastoma cell line expressing amyloid beta 1-42 (Abeta) and in rat embryonic cortical primary cell culture. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealing that ERK/RSK signaling pathway might mediate this effect of Gotu Kola extract. Taken together, we provide a possible molecular mechanism for memory enhancing property of Gotu Kola extract for the first time.
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PMID:Gotu Kola (Centella Asiatica) extract enhances phosphorylation of cyclic AMP response element binding protein in neuroblastoma cells expressing amyloid beta peptide. 1843 Oct 1

HDAC4 is a Class II histone deacetylase (HDAC) that is highly expressed in the brain, but whose functional significance in the brain is not known. We show that forced expression of HDAC4 in cerebellar granule neurons protects them against low potassium-induced apoptosis. HDAC4 also protects HT22 neuroblastoma cells from death induced by oxidative stress. HDAC4-mediated neuroprotection does not require its HDAC catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Neuroprotection by HDAC4 also does not require the Raf-MEK-ERK or the PI-3 kinase-Akt signaling pathways and occurs despite the activation of c-jun, an event that is generally believed to condemn neurons to die. The protective action of HDAC4 occurs in the nucleus and is mediated by a region that contains the nuclear localization signal. HDAC4 inhibits the activity of cyclin-dependent kinase-1 (CDK1) and the progression of proliferating HEK293T and HT22 cells through the cell cycle. Mice-lacking HDAC4 have elevated CDK1 activity and display cerebellar abnormalities including a progressive loss of Purkinje neurons postnatally in posterior lobes. Surviving Purkinje neurons in these lobes have duplicated soma. Furthermore, large numbers of cells within these affected lobes incorporate BrdU, indicating cell-cycle progression. These abnormalities along with the ability of HDAC4 to inhibit CDK1 and cell-cycle progression in cultured cells suggest that neuroprotection by HDAC4 is mediated by preventing abortive cell-cycle progression.
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PMID:HDAC4 inhibits cell-cycle progression and protects neurons from cell death. 1849 87

The Ras/Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, survival and apoptosis. The aim of this study was to determine the incidence of B-raf, Kirsten-ras (K-ras) and Neuroblastoma-ras (N-ras) gene mutations in esophageal squamous cell carcinoma (ESCC) in the Greek population. DNA was extracted from 30 ESCC and 32 normal esophageal specimens and screened for V600E B-raf, and K-ras/N-ras codon 12 mutations, by PCR-RFLP based analysis. Among the genes tested, only the heterozygous K-ras mutation was detected in 5 out of the 30 ESCC specimens (16%), whereas no mutation was found in the normal esophageal tissue (P < 0.022). The normal samples were screened negative for N-ras and V600E B-raf mutations. The increased risk of esophageal cancer was correlated with tobacco use (OR = 3.5, P < 0.023) and alcohol abuse (OR = 7.22, P < 0.001), accompanied with the high incidence of the k-ras codon 12 mutation (22%, OR = 1.77 and 21%, OR = 1.52), respectively. A similar positive association was seen in human papilloma virus (HPV)-infected patients (OR = 5.66, P < 0.003). Our overall findings demonstrate that the mutational activation of the K-ras gene, HPV infection and tobacco or alcohol abuse, can be considered independently or in combination as high risk factors for ESCC development.
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PMID:K-ras mutation, HPV infection and smoking or alcohol abuse positively correlate with esophageal squamous carcinoma. 1859 5

The effect of the potent soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) on neurite outgrowth and retraction was investigated in PC12 cells and SH-SY5Y human neuroblastoma cells. ODQ inhibited neurite outgrowth and triggered neurite retraction in the cells stimulated with nerve growth factor (NGF), staurosporine, or Y-27632. The nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had little effect on neurite outgrowth induced by Y-27632 or staurosporine. In the presence of ODQ, treatment of the cells with the cell-permeable cGMP analogue 8-bromo-cGMP failed to retrigger Y-27632- and staurosporine-induced neurite outgrowth. Furthermore, the depletion of sGC by RNA interference failed to prevent Y-27632- and staurosporine-induced neurite outgrowth. These results indicate that the NO/sGC/cGMP signaling cascade is not critically involved in ODQ-induced neurite remodeling. The MEK inhibitor PD98059 did not inhibit neurite outgrowth, and Y-27632 and staurosporine did not induce ERK phosphorylation, suggesting that the inhibitory effect of ODQ on neurite outgrowth is independent of the ERK signaling pathway. In contrast, pretreatment with dithionite or a hemin-glutathione mixture reversed the inhibitory effect of ODQ on Y-27632- and staurosporine-induced neurite outgrowth, indicating that ODQ might act on an intracellular redox-sensitive molecule. We conclude that ODQ inhibits Y-27632- and staurosporine-induced neurite outgrowth and triggers neurite retraction in an sGC-independent manner in neuronal cells and suggest that oxidation of unidentified redox-sensitive protein could be responsible for these effects.
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PMID:1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one inhibits neurite outgrowth and causes neurite retraction in PC12 cells independently of soluble guanylyl cyclase. 1871 50

NBS1 is a member of the Mre11-Rad50-NBS1 complex, which plays a role in cellular responses to DNA damage and the maintenance of genomic stability. Transgenic mice models and clinical symptoms of NBS patients have shown that NBS1 exerts pleiotropic actions on the growth and development of mammals. The present study showed that after repression of endogenous NBS1 levels using short interfering RNA, hTERT-RPE cells demonstrated impaired proliferation and a poor response to IGF-1. NBS1 down-regulated cells displayed disturbances in periodical oscillations of cyclin E and A and delayed cell cycle progression. Remarkably, lower phosphorylation levels of c-Raf and diminished activity of Erk1/2 in response to IGF-1 suggest a link among NBS1, IGF-1 signaling and the Ras/Raf/MEK/ERK cascade. The functional relevance of NBS1 in mitogenic signaling and initiation of cell cycle progression were demonstrated in NBS1 down-regulated cells where IGF-1 had a limited ability to induce the FOS and CCND1 expressions. In conclusion, our findings provide strong evidence that NBS1 has a functional role in IGF-1 signaling for the promotion of cell proliferation via the Ras/Raf/MEK/ERK cascade.
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PMID:NBS1 is required for IGF-1 induced cellular proliferation through the Ras/Raf/MEK/ERK cascade. 1879 19


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