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

Activation of the G-protein-coupled muscarinic (M3) receptor in human neuroblastoma SH-SY5Y cells is known to lead to phosphoinositol hydrolysis and noradrenaline release. In this study, the effect of carbachol on tyrosine phosphorylation and mitogen-activated protein (MAP) kinase activity in SH-SY5Y cells was examined. Carbachol concentration-dependently induced tyrosine phosphorylation of several proteins, including one of 42 kDa. This tyrosine-phosphorylated 42 kDa protein co-eluted from a Mono Q anion-exchange column with MAP kinase activity and with immunologically detected MAP kinase. Stimulation of tyrosine phosphorylation and activation of MAP kinase were also observed after incubation of cells with phorbol 12-myristate 13-acetate (PMA) and epidermal growth factor (EGF). Down-regulation or inhibition of protein kinase C (PKC) abolished the stimulatory effects of both carbachol and PMA on MAP kinase activity, whereas EGF-stimulated MAP kinase activity remained unaffected. Thus carbachol acting through the muscarinic (M3) receptor PKC-dependently induced tyrosine phosphorylation and activation of a 42 kDa MAP kinase in SH-SY5Y cells, whereas EGF-induced MAP kinase activation occurred independently of PKC.
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PMID:Stimulation of tyrosine phosphorylation and mitogen-activated-protein (MAP) kinase activity in human SH-SY5Y neuroblastoma cells by carbachol. 769 May 47

A gene encoding a putative third member of the insulin receptor family (called the insulin receptor-related receptor or IRR) was isolated in 1989. However, the naturally occurring protein product encoded by this gene has yet to be described. In the present studies, we have generated four monoclonal antibodies to a recombinantly expressed chimera, which contains the extracellular domain of human IRR. These antibodies were found to specifically recognize the chimeric IRR (and not the insulin or insulin-like growth factor I receptors), and two of the antibodies were capable of acting as partial agonists in the cells expressing the chimeric IRR. These antibodies have therefore been utilized to study the expression and properties of the native receptor. In contrast to the two other members of this receptor family, the endogenous IRR protein had only a very limited expression, being detected only in neuroblastomas. In primary neuroblastomas, the levels of the receptor were highest in samples from stage A tumors (those which are generally more highly differentiated and have higher levels of the nerve growth factor receptor). The endogenous IRR could also be detected in a neuroblastoma cell line (called IMR-5 cells). In these cells, IRR could be shown to be partly present as a hybrid with the insulin and insulin-like growth factor-I receptors but not with the receptor for nerve growth factor. The intrinsic tyrosine kinase activity of this endogenous IRR was activated by the agonist monoclonal antibody to IRR but not by nerve growth factor, insulin-like growth factor I, or insulin. Finally, this monoclonal antibody was found to stimulate mitogen-activated protein kinase activity in these cells. In summary, these studies demonstrate for the first time that the IRR protein is normally expressed, that its levels are highest in neuronal tissues, and that it can form hybrid receptors with the two other members of this receptor family but not with the more distantly related nerve growth factor receptor.
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PMID:Characterization of the endogenous insulin receptor-related receptor in neuroblastomas. 782 25

Nerve growth factor (NGF) is known to play a critical role in the differentiation and survival of normal sympathetic neurons through its interaction with a specific cell surface receptor. We analyzed ten well-characterized neuroblastoma cell lines for the expression and function of endogenous and exogenous p140TRK-A, and p75LNGFR. Exogenous LNGFR or TRK-A (or both) were introduced by transfection into three neuroblastoma cell lines. Transfected and untransfected neuroblastoma cell lines were analyzed by Northern analysis as well as tyrosine phosphorylation studies. Results indicate that endogenous TRK-A is expressed and/or p140TRK-A is phosphorylated in 10 of 10 cell lines. However, no other downstream responses to NGF stimulation (such as tyrosine phosphorylation of PLC gamma 1, PI-3 kinase, ERK1 and ERK2, induction of FOS and NGFI-A mRNAs, and neurite extension) were observed in the unresponsive cell lines. Transfection with p75LNGFR alone had no effect on responses to NGF stimulation. Three cell lines stably transfected with TRK-A exhibited early responses to NGF stimulation, but neurite extension was not observed. Our results indicate that endogenous TRK-A in non-responsive cell lines is either defective, or present in amounts below a threshold level required to elicit measurable responses to NGF. Furthermore, even after transfection with exogenous TRK-A, early responses were restored but later events such as neurite outgrowth did not occur, suggesting that downstream responsiveness is blocked as well.
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PMID:Expression and function of the nerve growth factor receptor (TRK-A) in human neuroblastoma cell lines. 797 9

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta family of growth factors, was first identified by its ability to promote the survival of midbrain dopaminergic neurons in culture. We demonstrate that GDNF treatment of several neuroblastoma cell lines leads to dose-dependent tyrosine phosphorylation of the RET receptor and that other transforming growth factor-beta family members are not able to activate the RET receptor. GDNF treatment of neuroblastoma cells also results in increased transcription of an Elk luciferase reporter gene, suggesting that GDNF activates the mitogen-activated protein kinase signal transduction pathway.
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PMID:Glial cell line-derived neurotrophic factor signals through the RET receptor and activates mitogen-activated protein kinase. 879 76

We have previously shown that 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), an inhibitor of protein kinase C, inhibits proliferation of neuroblastoma cells in culture. We have now tested whether the effect of H7 is mediated by MAP kinase and Raf. It is shown that, in Neuro 2a cells, activation of protein kinase C by addition of 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA), leads to phosphorylation of Raf and Mitogen-activated protein kinase (MAP kinase). PMA-induced phosphorylation of these proteins is prevented by H7. When quiescent Neuro 2a were stimulated to proliferate by addition of serum, Raf and MAP kinase were rapidly phosphorylated. Serum-induced phosphorylation of Raf and MAP kinase is prevented by H7. These results suggest that, in Neuro 2a cells, the control of proliferation by protein kinase C could be mediated by phosphorylation (and concomitant activation) of Raf and MAP kinase.
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PMID:H7, an inhibitor of protein kinase C, prevents serum-induced phosphorylation of Raf and MAP kinase in neuroblastoma cells. 887 20

Somatostatin possesses antisecretory and antiproliferative activity on some human tumors. We herein report that, in a human neuroblastoma cell line, the somatostatin analogue BIM 23014 inhibited mitogen-activated protein (MAP) kinase activity stimulated by either insulin-like growth factor-1, whose receptor bears a tyrosine kinase, or carbachol, which acts at a G-protein coupled receptor. In a human small cell lung carcinoma line BIM inhibited serum-stimulated MAP kinase activation. These inhibitory actions occur in a dose range quite similar to that observed for suppression of proliferation induced by the analogue in the same cell lines. The decrease in cAMP elicited by the analogue in the two cell lines is not responsible for its inhibitory action on MAP kinase and cell growth. Moreover, the analogue did not modify intracellular [Ca2+] and pH. An involvement of a phosphatase activity is suggested.
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PMID:A somatostatin analogue inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines. 895 39

Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in susceptible cells. To characterize the molecular events involved in Fas-induced apoptosis, we examined the contribution of two subgroups of the mitogen-activated protein (MAP) kinase family, the Jun kinases or stress-activated protein kinases (JNKs/SAPKs) and the extracellular signal-regulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. Here we show that both JNK and ERK protein kinases were activated upon Fas crosslinking through a Ras-dependent mechanism. Interference with either the JNK or ERK pathway by ectopic expression of dominant-interfering mutant proteins blocked Fas-mediated apoptosis. ERK activation was transient and associated with induced expression of the Fas receptor. In contrast, JNK activation was sustained and correlated with the onset of apoptosis. These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas. Inhibition of Fas killing by an interleukin 1beta-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation upon Fas ligation. In contrast, changes in Bcl-2 level due to expression of sense and antisense vectors influenced the sensitivity to Fas killing and Fas-induced JNK activation.
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PMID:Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. 909 88

Angiotensin II type 2 (AT2) receptors are involved in the inhibition of cell proliferation as well as in apoptosis and neuronal differentiation, through intracellular signalling pathways that remain poorly defined. The present study examines the effect of AT2-receptor stimulation on growth-factor-induced pathways leading to the activation of mitogen-activated protein (MAP) kinases. In N1E-115 neuroblastoma cells, AT2 receptors inhibit the activity of MAP kinases induced by serum as well as by epidermal growth factor. The inhibitory effect of angiotensin II (Ang II) is rapid and transient, and affects both ERK1 and ERK2 (extracellular signal-related protein kinase) isoforms of the enzyme. AT2-mediated MAP kinase inactivation is not sensitive to pertussis toxin or okadaic acid, but involves a vanadate-sensitive protein tyrosine phosphatase (PTP). Expression of MAP kinase phosphatase-1 (MKP-1) is not significantly modified upon AT2-receptor activation, and insensitivity to actinomycin D also rules out transcriptional induction of other MKPs as a possible mechanism for AT2-mediated inactivation of MAP kinases. In addition, we report here that both in N1E-115 cells and in Chinese hamster ovary cells expressing recombinant human AT2 receptors, Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors. These findings thus demonstrate functional negative cross-talk between heptahelical AT2 receptors and receptor tyrosine kinases, and suggest that SHP-1 tyrosine phosphatase is an early transducer of the AT2 receptor signalling pathway.
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PMID:Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase. 923 Jan 27

Rat pheochromocytoma cells, PC12 cells, undergo differentiation in response to nerve growth factor (NGF). Although the Ras-MAP kinase signaling pathway has been shown to play a central role in the response to NGF, the precise mechanism which induces differentiation remains unclarified. Recently, several gamma-lactam-related microbial products were identified to induce neurite outgrowth in neuroblastoma cells. Therefore, we synthesized a series of gamma-lactam-related compounds and tested for their ability to induce neurite outgrowth in PC12 cells. We found that two compounds, MT-19 and MT-20, induced neurite outgrowth at concentrations as low as 1 microg/ml. MT-19 and MT-20 have an n-hexadecyl group and an n-dodecyl group, respectively, at the position N-1 of the gamma-lactam ring, and the modification of this group leads to partial or complete loss of activity. In addition, the modification of the methyl and hydroxyl group at C-5 leads to complete loss of activity, indicating a strict structure-activity relationship. Interestingly, MT-19 and MT-20 induced neurite outgrowth of PC12 cells which lack normal Ras function. Furthermore, these compounds did not induce MAP kinase activation, suggesting that MT-19 and MT-20 do not require the Ras-MAP kinase signaling pathway which is shown to be necessary and sufficient for NGF-induced neurite outgrowth. Consistent with this, none of the early- or late-response genes tested, which include fos, zif268, Nur77, vgf, and transin, was induced. However, the protein level of three neurofilaments was increased after the incubation with these compounds. Since the level of other cytoskeleton proteins including actin and tubulin remained constant, MT-19 and MT-20 specifically affected neurofilament synthesis and/or turnover. Taken together, these findings indicate that MT-19 and MT-20 induce neurite outgrowth by activating the downstream target of MAP kinase or by a novel mechanism which is distinct from the NGF-activated pathway.
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PMID:Induction of neurite outgrowth in PC12 cells by gamma-lactam-related compounds via Ras-MAP kinase signaling pathway independent mechanism. 926 Aug 90

Insulin-like growth factor-I (IGF-I) induces neuronal differentiation in vitro. In the present study, we examined the signaling pathway underlying IGF-I-mediated neurite outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I induced concentration- and time-dependent tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and extracellular signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR phosphorylation was observed within 1 min, maximal phosphorylation of ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorylation were maintained for at least 24 h. Also, the concentration dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation paralleled that of IGF-I-mediated neurite outgrowth. We further examined the role of mitogen-activated protein kinase activation in IGF-I-stimulated neuronal differentiation using the mitogen-activated protein kinase/ERK kinase inhibitor PD98059. Whereas PD98059 had no effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ERK tyrosine phosphorylation and ERK phosphorylation of the substrate Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated neurite outgrowth. Finally, consistent with its ability to block neuronal differentiation, PD98059 inhibited IGF-I-dependent changes of GAP-43 and c-myc gene expression. Together these results suggest that activation of ERKs is essential for IGF-I-stimulated neuronal differentiation.
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PMID:Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. 926 Nov 37


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