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 c-Jun N-terminal kinase (JNK) signaling pathway is a key event in apoptosis. The cellular mechanisms underlying the control of JNK catalytic activity before and immediately after stress in neuronal cells are still not completely understood. Under resting conditions the basal activity of JNK is low, since JNK is kept inactive by the presence of one or more endogenous repressors, including glutathione S-transferase pi (GSTpi). The aim of this study was to investigate the control of JNK signaling by GSTpi. We examined the modifications of GSTpi protein expression and oligomerization after UV irradiation-induced stress in human SH-SY5Y neuroblastoma cells. In parallel, we investigated the effect of UV irradiation on JNK activation and c-Jun phosphorylation, and whether apoptosis represents a functional consequence triggered by this signaling pathway. We show that in SH-SY5Y cells JNK phosphorylation and activation precedes c-Jun phosphorylation and caspase-3 cleavage. Importantly, the increase of JNK enzymatic activity correlates with the dissociation of GSTpi-JNK complexes and the increased concentration of GSTpi multimer forms. Results presented herein show for the first time direct interaction between JNK and GSTpi in SH-SY5Y neuroblastoma cells, and suggest that in these cells GSTpi may serve as a regulator of JNK catalytic activity. This work contributes to further elucidate the mechanisms underlying the regulation of JNK activity under stress conditions.
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PMID:Glutathione S-transferase pi regulates UV-induced JNK signaling in SH-SY5Y neuroblastoma cells. 1915 63

Proteasome inhibitor, which inhibits NF-kappaB activation, has been reported to activate c-Jun N-terminal kinase (JNK)-c-Jun pathway. In this study, we investigated the effects of proteasome inhibitor on the human cytomegalovirus (HCMV) major immediate early (MIE) gene expression in human central nervous system (CNS)-derived cell lines. Treatment of HCMV-infected 118MGC glioma and U373-MG astrocytoma cells with three proteasome inhibitors, MG132, clasto-lactacystin beta-lactone, and epoxomicin, suppressed MIE protein expression. In contrast, in HCMV-infected IMR-32 neuroblastoma cells, the proteasome inhibitors increased MIE protein expression, even in the presence of NF-kappaB inhibitor SN-50. A luciferase reporter assay demonstrated that MG132 markedly elevated the MIE promoter/enhancer (MIEP) activity in IMR-32 cells, but down-regulated it in 118MGC and U373-MG cells. Mutation in five cAMP response elements (CREs) within the MIEP resulted in a loss of the ability to respond to MG132 in IMR-32 cells. Moreover, Western blotting analysis revealed that MG132 induced c-Jun phosphorylation in all three CNS-derived cell lines, whereas a high level of activating transcription factor-2 (ATF-2) phosphorylation was observed only in IMR-32 cells. Finally, MG132-induced MIE protein expression was suppressed by JNK inhibitor that reduced the phosphorylation levels of both c-Jun and ATF-2. Taken together, these results suggest that the proteasome inhibitors activate CRE binding proteins consisting of c-Jun and ATF-2 through activating the JNK-c-Jun pathway, thereby inducing MIE protein synthesis in IMR-32 cells under the condition where NF-kappaB activity is inhibited.
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PMID:Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines. 1920 84

We recently reported that LY294002 (LY29) and LY303511 (LY30) sensitized tumor cells to drug-induced apoptosis independent of the phosphoinositide 3-kinase/Akt pathway. Here, we investigated the mechanism of LY30-induced sensitization of human neuroblastoma cells to TRAIL-mediated apoptosis. We provide evidence that LY30-induced increase in intracellular H(2)O(2) up-regulates the expression of TRAIL receptors (DR4 and DR5) in SHEP-1 cells by activating mitogen-activated protein kinases, resulting in a significant amplification of TRAIL-mediated caspase-8 processing and activity, cytosolic translocation of cytochrome c, and cell death. Involvement of the death receptors was further confirmed by the ability of blocking antibodies against DR4 and/or DR5 to inhibit LY30-induced TRAIL sensitization. Pharmacologic inhibition of c-Jun NH(2) terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation by SP600125 and PD98059, respectively, blocked LY30-induced increase in sensitization to TRAIL-mediated death. Finally, small interfering RNA-mediated gene silencing of JNK and ERK inhibited LY30-induced increase in surface expression of DR4 and DR5, respectively. These data show that JNK and ERK are two crucial players involved in H(2)O(2)-mediated increase in TRAIL sensitization of tumor cells upon exposure to LY30 and underscore a novel mode of action of this inactive analogue of LY29. Our findings could have implications for the use of LY30 and similar compounds for enhancing the apoptotic sensitivity of neuroblastoma cells that often become refractory to chemotherapy.
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PMID:LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. 1922 50

Estradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these "genomic effects", estrogen may also act as a more general "trophic factor" triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with beta-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates beta-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of beta-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS).
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PMID:Estradiol activates beta-catenin dependent transcription in neurons. 1936 Jan 3

Investigation of the c-Jun N-terminal kinases (JNKs) has mainly focused on their response to stress and their pro-apoptotic effects. In this regard, JNKs are crucial mediators of chemotherapy-induced killing of tumor cells. Importantly, however, JNKs also have physiological functions in cancer involving cell cycle regulation or oncogenesis. Hypothetically, the composition of JNK signalosomes determines the signaling outcome which,in turn, implies a multitude of different, sometimes opposing and interfering functions. In the present study,the well-characterized human neuroblastoma cell line SH-SY5Y served as a model system to separate physiological and pro-apoptotic JNK actions in the response to the cytoskeleton-interfering substances colchicine, cytochalasin D and taxol. Basically, JNKs mediated both cell death and proliferation. Using the chemical JNK inhibitor SP600125 as well as compartment-specific JNK-inhibiting constructs and dominant negative isoform mutants, we show that the nuclear subgroup of JNK2 is the dominant effector in colchicine and taxol-induced apoptosis, while cell cycle promotion is mediated by both cytoplasmic and nuclear JNK2.In contrast, cytochalasin D-triggered apoptosis is independent of JNK signaling. Interestingly, the data of the present study demonstrate for the first time that both cell protective (cell cycle progression) and destructive mechanisms (apoptosis) are simultaneously controlled by a single JNK isoform in the same cell system even under the influence of one stimulus. This has implications for the therapeutic application of JNK inhibitors and cytoskeleton-interfering substances in oncologic disorders.
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PMID:Concurrent protective and destructive signaling of JNK2 in neuroblastoma cells. 1938 49

Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements, taken for its multivalent properties. In this study, dosage effects of EGb761 on hydrogen peroxide (H(2)O(2))-induced apoptosis of human neuroblastoma SH-SY5Y cells were investigated. It was found that H(2)O(2)-induced apoptotic cell death in SH-SY5Y cells, which was revealed in DNA fragmentation, mitochondrial membrane potential depolarization, and activation of Akt, c-Jun N-terminal kinases (JNK) and caspase 3. Low doses of EGb761 (50-100 microg/ml) inhibited H(2)O(2)-induced cell apoptosis via inactivation of Akt, JNK and caspase 3 while high doses of EGb761 (250-500 microg/ml) enhanced H(2)O(2) toxicities via inactivation of Akt and enhancement of activation of JNK and caspase 3. Additional experiments revealed that H(2)O(2) decreased intracellular GSH content, which was also inhibited by low concentrations of EGb761 but enhanced after high concentrations of EGb761 treatment. This further suggests to us that dosage effects of EGb761 on apoptotic signaling proteins may be correlated with regulation of cell redox state. Therefore, treatment dosage may be one of the vital factors that determine the specific action of EGb761 on oxidative stress-induced cell apoptosis. To understand the mechanisms of dosage effects of EGb761 may have important clinical implications.
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PMID:Dosage effects of EGb761 on hydrogen peroxide-induced cell death in SH-SY5Y cells. 1941 4

Penta-acetyl geniposide [(Ac)(5)GP], an acetylated geniposide product from Gardenia fructus, has been known to have hepatoprotective properties and recent studies have revealed its anti-proliferative and apoptotic effect on C6 glioma cells. In this study, we first report the anti-metastastic effect of (Ac)(5)GP in the rat neuroblastoma line: C6 glioma cells. First (Ac)(5)GP exhibited an inhibitory effect on abilities of adhesion and motility by cell-matrix adhesion assay, wound healing assay and Boyden chamber assay. Second, the decreasing activity of matrix metalloproteinase-2 (MMP-2) was noted by gelatin zymography assay. Further analysis with semi-quantitative RT-PCR showed the mRNA levels of MMP-2 and membrane type I matrix metalloproteinase (MT1-MMP) were significantly reduced, while the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) was elevated by (Ac)(5)GP treatment. Further (Ac)(5)GP also exerted an inhibitory effect on phosphoinositide 3-kinase (PI3K) protein expression, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inhibition of activation of transcription factor nuclear factor kappa B (NF-kappaB), c-Fos, c-Jun. These findings proved (Ac)(5)GP is highly likely to be a inhibiting cancer migration agent to be further developed in the future.
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PMID:Inhibitory effect of penta-acetyl geniposide on C6 glioma cells metastasis by inhibiting matrix metalloproteinase-2 expression involved in both the PI3K and ERK signaling pathways. 1946 79

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in MPP(+)-induced neurotoxicity. We show that NF-kappaB was activated by MPP(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF-kappaB partially mediated the neurotoxicity of MPP(+), as suggested by the reduction of MPP(+)-induced cell death by both a specific IkappaB kinase (IKK) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon MPP(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP(+)-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as MPP(+)-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP(+)-induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy.
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PMID:NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1. 1977 65

Tyrosine hydroxylase (TH) is expressed specifically in catecholaminergic cells and is transcriptionally activated via a protein kinase C (PKC)-dependent pathway. To identify regulatory regions of the TH gene, transfected neural crest-derived catecholaminergic cells [human neuroblastoma SH-SY5Y and bovine adrenal medullary (BAM) cells] or glia-derived SF-763 cells were used to analyze expression of a chloramphenicol acetyltransferase (CAT) reporter gene under the control of 5'-flanking sequences of the bovine TH gene. Plasmid pTH(-245/+21)CAT was constructed by fusing the -245 to +21 region of the TH gene to CAT sequences in the promoterless pCAT basic plasmid. Cells transfected with pTH(-245/+21)CAT expressed CAT activity at levels 8- to 100-fold higher than those of cells transfected with pCAT basic. In SH-SY5Y or BAM cells, pTH(-245/+21)CAT supported the expression of CAT at levels similar to or higher than that supported by the tissue nonspecific viral SV40 promoter/enhancer. In glia-like cells, CAT expression from pTH(-245/+2 1)CAT was about 13-fold lower than that under the control of the SV40 promoter. Incubation of neuroblastoma cells with the active phorbol ester, phorbol 12-myristate 13-acetate (PMA), increased expression of CAT from pTH(-245/+2 1)CAT over 6-fold and was accompanied by induction of c-fos and c-jun mRNAs and proteins. The regulation of TH promoter function by c-Fos/c-Jun was corroborated by transactivation of the TH promoter in SH-SY5Y cells engineered to overexpress exogenous c-Fos and c-Jun. TH gene sequences essential for c-Fos/c-Jun transactivation were located in the -245 to -52 region, upstream from a CRE-like element. Gel mobility assays demonstrated binding of c-Fos-antigen(s) to the region of the TH promoter that supports activation by PMA and c-Fos/c-Jun. Temporal patterns of nicotinic agonist-stimulated induction of c-fos and TH mRNA are also consistent with a role for c-Fos in TH gene transcription. Our results demonstrate that the 5'-flanking region of the bovine TH gene operates as an authentic promoter capable (i) of directing cell-specific expression of a bacterial CAT gene and (ii) of conferring responsivity to PKC-stimulation. The results also suggest that the nuclear proteins c-Fos and c-Jun contribute to PKC pathway-mediated activation of the TH gene via direct interaction with the TH gene promoter. The activation of TH gene expression by PKC/c-Fos/c-Jun may serve as an additional or alternative mechanism to activation by the cAMP-CRE pathway.
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PMID:A 5'-flanking region of the bovine tyrosine hydroxylase gene is involved in cell-specific expression, activation of gene transcription by phorbol ester, and transactivation by c-Fos and c-Jun. 1991 82

Mu-opioid receptor expression increases during neurogenesis, regulates the survival of maturing neurons and is implicated in ischemia-induced neuronal death. The repressor element 1 silencing transcription factor (REST), a regulator of a subset of genes in differentiating and post-mitotic neurons, is involved in its transcriptional repression. Extracellular signaling molecules and mechanisms that control the human mu-opioid receptor (hMOR) gene transcription are not clearly understood. We examined the role of protein kinase C (PKC) on hMOR transcription in a model of neuronal cells and in the context of the potential influence of REST. In native SH-SY5Y neuroblastoma cells, PKC activation with phorbol 12-myristate 13-acetate (PMA, 16 nM, 24h) down-regulated hMOR transcription and concomitantly elevated the REST binding activity to repressor element 1 of the hMOR promoter. In contrast, PMA activated hMOR gene transcription when REST expression was knocked down by an antisense strategy or by retinoic acid-induced cell differentiation. PMA acts through a PKC-dependent pathway requiring downstream MAP kinases and the transcription factor AP-1. In a series of hMOR-luciferase promoter/reporter constructs transfected into SH-SY5Y cells and PC12 cells, PMA up-regulated hMOR transcription in PC12 cells lacking REST, and in SH-SY5Y cells either transfected with constructs deficient in the REST DNA binding element or when REST was down-regulated in retinoic acid-differentiated cells. These findings help explain how hMOR transcription is regulated and may clarify its contribution to epigenetic modifications and reprogramming of differentiated neuronal cells exposed to PKC-activating agents.
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PMID:Transcription factor REST negatively influences the protein kinase C-dependent up-regulation of human mu-opioid receptor gene transcription. 1991 83


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