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: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory pain is counteracted by a number of physiological processes. For example, opioid receptors, which are present on peripheral terminals of sensory neurons, are activated by endogenous opioids, which are released from immune cells migrating to the inflamed tissue. Earlier data demonstrated that interleukin-6 contributes to such inflammation-induced analgesia. In this report, we demonstrated that interleukin-6 strongly induces mu-opioid receptor mRNA in the human neuroblastoma cell line SH SY5Y, whereas delta-opioid receptor mRNA levels are not influenced. The mRNA increase in these cells is followed by an increase in mu-opioid receptor-specific binding. Using transcription factor decoy oligonucleotides, direct evidence was provided that the up-regulation of mu-opioid receptor mRNA in intact cells is dependent on the transcription factors signal transducers and activators of transcription 1 (STAT1) and STAT3, whereas other transcription factors, such as activator protein-1, nuclear factor (NF)-kappaB, or NF-interleukin-6 are not involved. STAT1 and STAT3 bound to a site located at nucleotide -1583 on the promoter of the human mu-opioid receptor gene, as shown by transient transfection experiments, electrophoretic mobility shift assays, and transcription factor decoy oligonucleotides. A mutation analysis of the 5'-TTCATGGAA-3' STAT1/3 element (palindrome underlined) was performed to determine nucleotide residues that are necessary for the binding of STAT1 and STAT3. It suggested that only the palindromic half sides and the two adjacent central nucleotides are required. Neither mutation of the nucleotides outside the palindrome nor mutation of the central nucleotide affected STAT1/3 binding.
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PMID:Transcriptional regulation of the human mu-opioid receptor gene by interleukin-6. 1544 91

We have shown recently that in human T lymphocytes, leptin stimulates activity and expression of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), through STAT3 (signal transducer and activator of transcription 3) and its CRE (cAMP response element)-like transcriptional target in the FAAH promoter [Maccarrone, M., Di Rienzo, M., Finazzi-Agro, A., & Rossi, A. (2003) J. Biol. Chem. 278, 13318-13324]. We have also shown that progesterone, alone or additively with leptin, up-regulates the FAAH gene in human T-cells, through the Ikaros transcription factor [Maccarrone, M., Bari, M., Di Rienzo, M., Finazzi-Agro, A., & Rossi, A. (2003) J. Biol. Chem. 278, 32726-32732]. Here, we extend these observations to immortalized human lymphoma U937 cells, where stimulation of FAAH by leptin (up to approximately 300% of the controls) involves binding to a leptin receptor (Kd = 2.0 +/- 0.1 nm, Bmax = 382 +/- 5 fmol.mg protein(-1), apparent molecular mass of approximately 110 kDa), and stimulation by progesterone involves an intracellular receptor of approximately 120 kDa. Unlike FAAH, the other proteins of the endocannabinoid system are not modulated by the two hormones. Interestingly, human neuroblastoma CHP100 cells also have a leptin receptor (approximately 110 kDa, Kd = 2.2 +/- 0.2 nm, Bmax = 339 +/- 8 fmol.mg protein(-1)), a progesterone receptor (approximately 120 kDa), STAT3 and Ikaros, yet their FAAH is not activated by leptin or progesterone. These data, corroborated by transient expression and electrophoretic mobility-shift assays, demonstrate an unprecedented cell-specific regulation of the FAAH gene, which has important implications for the control of tone and activity of AEA along the neuroimmune axis.
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PMID:Differential regulation of fatty acid amide hydrolase promoter in human immune cells and neuronal cells by leptin and progesterone. 1560 54

Janus kinases (JAK) and signal transducers and activator of transcription (STAT) proteins are activated in response to many cytokines and growth factors and are well studied in the immune system. This study was conducted to examine the role of the JAK/STAT pathway in neurons in response to tumor necrosis factor-alpha (TNFalpha) and insulin-like growth factor-1 (IGF-1), which play a major role during neurodegeneration, and to study their effect on expression of suppressors of cytokine signaling 3 (SOCS-3), belonging to the novel family of feedback regulators of cytokine and growth factor activities. In this report, we showed that TNFalpha is inhibitory to the survival of primary cortical neurons at higher doses and that IGF-1 can rescue TNFalpha-stimulated cell death. We showed that the JAK/STAT pathway is involved in this rescue as tyrphostin AG490, a specific inhibitor of JAK/STAT, completely inhibits cell survival in response to IGF-1. STAT3 gets tyrosine-phosphorylated and translocated to the nucleus in response to IGF-1. Northern blot, semi-quantitative reverse transcription-PCR, and real time PCR experiments demonstrated that the JAK/STAT pathway also up-regulated SOCS-3 mainly in response to IGF-1. SOCS-3 associated with the IGF receptor and blocked further STAT3 activation. To our knowledge, this is the first report that demonstrated the importance of the JAK/STAT pathway and the role of SOCS-3 in the survival of neurons in response to IGF-1. We have subsequently shown that SOCS-3 overexpression, on one hand, leads to neuroblastoma cell death and on the other hand leads to primary cell differentiation, indicating the involvement of SOCS-3 in cell survival and differentiation.
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PMID:JAK/STAT3 pathway is involved in survival of neurons in response to insulin-like growth factor and negatively regulated by suppressor of cytokine signaling-3. 1599 44

Cadmium is an environmental contaminant producing numerous pathological effects including neurological disorders. The mechanisms through which cadmium produces neurotoxicities are not completely known. We found that divalent cadmium (CdCl2) inhibited ciliary neurotrophic factor (CNTF)-mediated Jak1 and Jak2 tyrosine kinase signaling in human BE(2)-C neuroblastoma cells. CdCl2 concentrations as low as 0.1 microM and for times as brief as 2 h significantly reduced CNTF-induced tyrosine phosphorylation of both STAT1 and STAT3, the principle substrates of Jak kinases in neurons. The phosphorylation of STAT1 by interferon-gamma was also inhibited by CdCl2. However, activation of the fibroblast growth factor receptor tyrosine kinase was not inhibited by CdCl2. Jak/STAT signaling was inhibited by CdCl2 selectively in cultures of chick retina neurons and neuroblastoma cells, whereas signaling in the nonneuronal cells HepG2 and chick skeletal myotubes was not affected. Results using dichlorofluorescein indicated CdCl2 increased cellular oxidative stress, and all of these effects of CdCl2 were protected against by pretreatment with antioxidants. Neuronal inhibition of Jak kinase by CdCl2-induced oxidative stress is a new mechanism of cadmium action which may directly produce neurotoxic symptoms as well as implicate cadmium and related metals as environmental factors in the etiology of neurodegenerative diseases.
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PMID:Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress. 1684 30

The actions of the neuropoietic cytokines are mediated by the gp130 receptor, which activates several signaling molecules including the transcription factor STAT3 (signal transducer and activator of transcription), which, in turn, is subject to feedback inhibition by SOCS3 (suppressor of cytokine signaling). Activation of the gp130 receptor has been implicated in axonal growth particularly during regeneration, but the specific contribution of STAT3 is the subject of conflicting reports. Measurements of SOCS3 mRNA in rat dorsal root ganglia showed a significant induction in this inhibitory molecule after peripheral nerve injury. The functions of STAT3 and SOCS3 in adult rat primary sensory neurons were investigated in vitro through transduction of lentiviruses yielding a conditionally activated STAT3, native SOCS3, or a mutant SOCS3 with dominant-negative actions. The SOCS3 construct was effective in inhibiting tyrosine phosphorylation of STAT3 in a neuroblastoma cell line and in blocking nuclear accumulation of endogenous STAT3 or of the conditionally activated STAT3 chimera in primary sensory neurons. In such neurons, transduction and activation of STAT3 enhanced neurite growth, transduction with SOCS3 reduced neurite outgrowth, and transduction with mutant SOCS3 enhanced neurite growth, at least under basal conditions. In conclusion, STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes, and SOCS3 is detrimental to axonal growth through inhibition of STAT3 and/or other transcription factors.
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PMID:Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons. 1697 35

Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
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PMID:Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. 1771 Feb 28

Transduction and activation of an inducible form of STAT3 (signal transducer and activator of transcription) sufficed to increase VIP (vasoactive intestinal protein) mRNA concentrations in neuroblastoma cells. Overexpression of SOCS3 (suppressor of cytokine signaling) inhibited and mutant SOCS3 (with an inactivating point mutation in amino acid 25) enhanced the induction of VIP mRNA by CNTF (ciliary neurotrophic factor). Because mutant SOCS3 did not augment the increase in STAT transcriptional activity following CNTF stimulation, the enhancement by mutant SOCS3 of the actions of CNTF cannot be attributed to changes in STAT3 signaling. Mutant SOCS3 increased AP-1 (activator protein) transcriptional activity and JNK (c-Jun N-terminal kinase) activity and SOCS3 bound to the scaffolding protein, JNK-interacting protein-1: these observations provide a plausible explanation for the enhancement by mutant SOCS3 of the actions of CNTF. We conclude that endogenous SOCS3 inhibits AP-1 activity through blocking of JNK phosphorylation.
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PMID:SOCS3 suppresses AP-1 transcriptional activity in neuroblastoma cells through inhibition of c-Jun N-terminal kinase. 1805 17

The adipocyte-derived hormone leptin plays a critical role in a variety of physiological and pathological actions. As such the determination of leptin signal transduction pathways are important both for understanding the molecular mechanisms of leptin action and for identifying sites for possible therapeutic intervention. Since the hypothalamus is the primary site of leptin action, we sought to identify a neuronal-derived human cell line containing the long form of the leptin receptor (OBRb). To this end, we screened several neuroblastoma cell lines and isolated a sub-line of SH-SY5Y cells, which we designated as SH-OBRb, for further studies. We characterized the transduction pathways induced by leptin in SH-OBRb cells and demonstrated that OBRb mediates tyrosine phosphorylation of STAT3, phosphorylation of ERK1/2, but not SAPK/JNK and p38 MAPK, in a dose and time dependent fashion. In addition, Akt appears to be phosphorylated in the basal state and to be insensitive to further activation by leptin. In summary, we have isolated a unique cell line that can be utilized as a model for use in the study of leptin action and molecular mechanisms.
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PMID:Identification and characterization of a leptin-responsive neuroblastoma cell line. 1912 99

As a natural product, (-)-Epigallocatechin-3-gallate (EGCG), has demonstrated remarkable neuronal protection by depressing oxidative stress in Parkinson's disease (PD). However, the molecular mechanisms underlying EGCG neuronal protection have not been clarified. Using 6-hydroxydopamine (6-OHDA)-treated human neuroblastoma SH-SY5Y cells as a PD cell model, we found that 6-OHDA can cause neuronal death by regulating the activity of STAT3. Pretreatment of SH-SY5Y cells with EGCG (0.1-10 microM) significantly attenuated cell death induced by 6-OHDA. In addition, STAT3 activity decline induced by 6-OHDA in SH-SY5Y cells can be completely prevented by the presence of 1 microM of EGCG, and neuronal cell proliferation can be stimulated by EGCG treatment. These results clearly demonstrate that the disruption of STAT3 signaling by 6-OHDA makes significant contribution to the neuronal death in PD, and the protection of EGCG on neurons against oxidative stress-induced cell death may result from the re-stimulation of STAT3 signaling pathway. Our study not only clarified the role of STAT3 signaling pathway in oxidative stress-induced neuronal cell death, but also identified its involvement in the protection mechanism of EGCG on neurons in PD. The data resulting from our study also suggest that STAT3 may serve as a potential therapeutic target for drug development in PD.
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PMID:(-)-Epigallocatechin-3-Gallate protects SH-SY5Y cells against 6-OHDA-induced cell death through STAT3 activation. 1922 5

Although the role of 1alpha,25-dihydroxyvitamin D3 in calcium homeostasis of bone tissue is clear, evidence of the involvement of vitamin D3 in the central nervous system functions is increasing. In fact, vitamin D3 regulates vitamin D receptor and nerve growth factor expression, modulates brain development, and reverses experimental autoimmune encephalomyelitis. Only few studies, however, address vitamin D3 effect on embryonic hippocampal cell differentiation. In this investigation, the HN9.10e cell line was used as experimental model; these cells, that are a somatic fusion product of hippocampal cells from embryonic day-18 C57BL/6 mice and N18TG2 neuroblastoma cells, show morphological and cytoskeletal features similar to their neuronal precursors. By this model, we have studied the time course of vitamin D3 localization in the nucleus and its effect on proteins involved in proliferation and/or differentiation. We found that the translocation of vitamin D3 from cytoplasm to the nucleus is transient, as the maximal nuclear concentration is reached after 10 h of incubation with (3)H-vitamin D3 and decreases to control values by 12 h. The appearance of differentiation markers such as Bcl2, NGF, STAT3, and the decrease of proliferation markers such as cyclin-1 and PCNA are late events. Moreover, physiological concentrations of vitamin D3 delay cell proliferation and induce cell differentiation of embryonic cells characterized by modification of soma lengthening and formation of axons and dendrites.
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PMID:Effect of 1alpha,25-dihydroxyvitamin D3 in embryonic hippocampal cells. 1960 26


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