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)

Protein kinase C (PKC) is a serine/threonine kinase which is thought to play an important role in cellular proliferation and differentiation. PKC activity is stimulated physiologically by diacylglycerol and experimentally by phorbol esters. Long-term exposure of human neuroblastoma cells to phorbol esters results in down-regulation of PKC activity and induction of neuronal differentiation. In this study, we explored the hypothesis that reduced PKC expression is necessary for differentiation of the human neuroblastoma cell line SK-N-SH. PKC activity and PKC-alpha mRNA levels were assayed in cultured SK-N-SH cells over a period of several days in the presence or absence of serum. These determinants of PKC expression were compared with several known markers of neuroblastoma differentiation, including neurite outgrowth and steady-state levels of c-myc and GAP43 mRNA. We observed steady losses of PKC activity and PKC-alpha mRNA content after transfer of cells to serum-free or chemically defined media. However, morphological and biochemical differentiation of SK-N-SH cells occurred only in chemically defined medium, perhaps due to the presence of insulin. We conclude that while loss of PKC may be associated with neuroblastoma differentiation, diminished PKC alone is not sufficient to induce or support the differentiation process.
 ...
PMID:PKC activity and PKC-alpha mRNA content are reduced in serum-derived human neuroblastoma cells without concomitant induction of differentiation. 834 86

Ciliary neurotrophic factor (CNTF)-dependent induction of expression of the neuropeptide vasoactive intestinal peptide (VIP) gene is mediated by a 180-base pair cytokine response element (CyRE) in the VIP promoter. To elucidate the molecular mechanisms mediating the transcriptional activation by CNTF, intracellular signaling to the CyRE has been studied in a neuroblastoma cell line. It has been shown previously that CNTF induces Stat proteins to bind to a site within the CyRE. CNTF also induces a second protein to bind to a C/EBP-like site within the CyRE. In this report, we show that this inducible CyRE binding protein is composed of the AP-1 proteins c-Fos, JunB, and JunD. These proteins bind to a non-canonical AP-1 site located near the previously characterized C/EBP site. The serine/threonine kinase inhibitor H7 prevents CNTF-dependent induction of AP-1 binding and CyRE-mediated transcription, suggesting that an H7-sensitive kinase is important to mediating CNTF effects on VIP transcription. The integration at the VIP CyRE of the Jak-Stat and AP-1 signaling pathways with other pre-existing proteins provides a cellular mechanism for cell- and cytokine-specific signaling.
 ...
PMID:Integration of Jak-Stat and AP-1 signaling pathways at the vasoactive intestinal peptide cytokine response element regulates ciliary neurotrophic factor-dependent transcription. 909 93

Human glycogen synthase kinase-3 alpha (GSK-3 alpha) is a serine/threonine kinase that phosphorylates a variety of cytoplasmic and nuclear proteins. It also phosphorylates components of the neuronal cytoskeleton including tau and neurofilament heavy chain. Hyperphosphorylated tau is found in neurofibrillary tangles, a hallmark of Alzheimer's disease and aberrant phosphorylation of neurofilament heavy chain is observed in motor neuron disease. Alterations in GSK-3 alpha activity may therefore contribute to the disease process in these disorders. As a first step to understand the transcriptional regulation of GSK-3 alpha, a 2-kb (p-1751/+243) DNA fragment upstream of the GSK-3 alpha initiation codon was obtained from a YAC clone and characterised. Using primer extension assays, a putative transcriptional start site was located to a G nucleotide 244 bp upstream of the ATG codon. Several transcription factor-binding sites were identified on the promoter region, but no TATA-like element was located close to the start site. Deletion mutants of the 2-kb DNA fragment were generated and fused to a promoterless chloramphenicol acetyltransferase (CAT) gene. Transfection study in a neuroblastoma cell line revealed the 1-kb (p-719/+243) fragment carried strong promoter activity, while the 2-kb construct that contains an Alu-like sequence was only 50% active.
 ...
PMID:Molecular cloning and expression analysis of human glycogen synthase kinase-3 alpha promoter. 1111 43

Insulin-like growth factor I (IGF-I) protects cells from apoptosis primarily through the action of phosphatidylinositol-3 kinase and the downstream serine/threonine kinase Akt. The PTEN gene product, a protein which dephosphorylates phosphatidylinositol lipids, prevents activation of Akt and regulates several cellular functions, including cell cycle progression, cell migration, and survival from apoptosis. In this study, PTEN overexpression decreases IGF-I-induced Akt activity, enhances serum withdrawal-induced apoptosis, and decreases IGF-I protection and cell growth in SHEP cells. The PTEN lipid phosphatase mutant G129E fails to inhibit IGF-I-stimulated Akt activity and protection from apoptosis. The C124S mutation, which abolishes both lipid and protein phosphatase activity, fails to inhibit Akt activity and IGF-I protection against hyperosmotic-induced apoptosis but still inhibits growth and IGF-I protection against serum withdrawal-induced apoptosis. These data suggest a role for PTEN in modulating the effect of IGF-I on Akt activity, neuroblastoma cell growth, and protection against apoptotic stimuli.
 ...
PMID:PTEN/MMAC1 overexpression decreases insulin-like growth factor-I-mediated protection from apoptosis in neuroblastoma cells. 1145 34

Sequences of two recently cloned genes playing a role in resistance against wheat pathogens (receptor-like kinase Lrk10 and Cre3 genes) were used to search for similarity of cereal clones included in the NCBI database. We found 23 clones with similarity to the Cre3 gene with predicted NBS and LRR domains, and 50 clones with serine/threonine kinase function and similarity to the new receptor-like kinase gene Lrk10 from wheat. In those two groups of clones some conservative nucleotide sequences were identified. Two sequences are identical between the majority of resistance gene candidate clones with a high similarity to Lrk10, and two sequences are identical between the majority of resistance gene candidate clones with similarity to the Cre3 gene.
 ...
PMID:Putative resistance genes of cereals: structure and expected function. 1217 19

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
 ...
PMID:Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. 1292 38

In pediatric solid tumors, such as neuroblastoma (NB), it has been reported that the frequency of TP53 gene alterations is lower than that in adult tumors, suggesting that other tumor suppressor genes may play more important roles in the development of pediatric solid tumors. The CHK2 gene, whose product is a checkpoint kinase that plays a central role in DNA damage response and acts upstream of TP53, has been found to be mutated in a subset of Li-Fraumeni syndrome without mutations of TP53 and in some other sporadic human tumors, earmarking this serine/threonine kinase as a candidate tumor suppressor gene. Thus, we analyzed the CHK2 gene to address whether it is a candidate tumor suppressor gene for pediatric solid tumors. We screened for mutations of the CHK2 gene in 25 NB, 8 rhbdomyosarcoma, 12 Ewing sarcoma, and 26 other pediatric solid tumor cell lines as well as 77 fresh tumors including two cases of multiple cancers. Using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis and reverse transcriptase (RT)-PCR-SSCP followed by direct sequence analysis, we detected only one missense mutation (S505T) in one NB cell line and two silent mutations in one NB cell line and one NB fresh tumor, respectively. Through RT-PCR and subcloning analysis, we detected a similar expression of the CHK2 gene in all of the NB cell lines and fresh tumors; however, we identified at least three isoforms of the CHK2 gene, two of which have not been reported previously. These results suggest that aberrations of the CHK2 gene are rare in pediatric solid tumors.
 ...
PMID:Aberrations of the CHK2 gene are rare in pediatric solid tumors. 1594 82

Membrane-associated guanylate kinases (MAGUKs) are cytoplasmic multi-domain proteins that serve as scaffold proteins at cell junctions and synapses. Calmodulin-associated serine/threonine kinase (CASK) stabilizes the integrity of synapses in the brain. Additionally, CASK is capable of acting as a transcriptional co-activator and localizes to neuronal nuclei in the developing brain. We have recently described CASK localization to both the pre- and post-synaptic membranes of the neuromuscular junction (NMJ), where it forms a complex with discs large (Dlg). CASK also localizes to some, but not all nuclei in adult mouse skeletal muscle. To begin to dissect the roles of CASK in the cellular components of the NMJ, we investigated the localization of CASK during differentiation in cell culture models of skeletal muscle and motor neurons. We demonstrate that CASK localizes to the nucleus in undifferentiated myoblasts, but is pre-dominantly in the cytoplasm in differentiated myotubes of the C2C12 myogenic cell line. We also show nuclear localization of both CASK and Dlg in a motor neuron-neuroblastoma hybrid cell line, MN-1, suggesting a role for CASK and Dlg in nuclei of neurons in the peripheral nervous system. Finally, we demonstrate that CASK and Dlg do not co-cluster with acetylcholine receptors in C2C12 myotubes in response to agrin or laminin treatment, suggesting a novel mechanism of recruitment to the NMJ that is independent of acetylcholine receptor and utrophin complexes. These studies delineate important developmental characteristics of CASK and Dlg, and suggest dual roles for these proteins in both the skeletal muscle and motor neuron components of the NMJ.
 ...
PMID:CASK localizes to nuclei in developing skeletal muscle and motor neuron culture models and is agrin-independent. 1596 5

Choline kinase (ChoK) is a cytosolic enzyme present in various tissues, which catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is important for the generation of two major membrane phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM) and subsequently for the cell division. ChoK plays a vital role in cell signaling pathways and regulation of cell growth along with PCho involved in malignant transformation through ras oncogenes in different cancers such as breast, lung, colon, prostate, neuroblastoma, hepatic lymphomas, meningiomas and diverse murine tumours. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are involved in the activation of ChoK during tumorigenesis. ChoK gene induction seems to be associated with certain cell stress or cell defense. Nowadays, RNAi appear to be one of the most promising routes in the cancer therapy. The anticancer potential of both stable expression of siRNAs and their high sequence specificity by RNAi mediated suppression of oncogenic ras in human pancreatic carcinoma, human melanomas and ovarian cancer has been observed. It has an important role in sequence specific post-transcriptional gene silencing mechanism. Presently, the crystal structure of Caenorhabditis elegans choline kinase A-2 (ChoKA-2) is available, which may be useful for comparative modeling of human ChoK and further modeling studies. The present review aims at the general overview of importance, expression, structure, progress in molecular modeling, active site analysis and inhibitors of ChoK. It also highlights the recent role of ChoK in various types of Ras-dependent and Ras-independent carcinogenesis.
 ...
PMID:Choline kinase: an important target for cancer. 1671 78

Arsenic is an environmental toxicant that recently has been shown to have anticancer activity against a number of types of cancer cells by inducing apoptosis. Glycogen synthase kinase-3 (GSK3), a serine/threonine kinase, is an important pro-apoptotic signaling enzyme. Although GSK3 has been shown to promote apoptosis caused by a wide variety of insults, a role for GSK3 in arsenic-induced apoptosis has not yet been identified. Investigation of the involvement of GSK3 in arsenite-induced apoptosis demonstrated that arsenite induced apoptosis in SH-SY5Y human neuroblastoma cells, activating the executioner caspase-3 which caused cleavage of poly-ADP ribose-polymerase (PARP). Two selective GSK3 inhibitors, lithium and SB216763, attenuated caspase-3 activation and PARP cleavage induced by arsenite treatment indicating that GSK3 contributed to arsenite-induced apoptosis. Apoptotic signaling following exposure to arsenite involved cytochrome C release from mitochondria, and this was reduced by inhibition of GSK3 indicating that GSK3 promotes arsenite-induced apoptotic signaling upstream of mitochondrial disruption. Moreover, arsenite induced the translocation of Bax and p53 to the mitochondria and the activation-associated oligomerization of Bax, and these crucial events were reduced by inhibition of GSK3, indicating that GSK3 promotes arsenite-induced apoptosis by facilitating signals leading to mitochondrial apoptotic events. Taken together, the findings from this study reveal that GSK3 promotes arsenite-induced apoptosis by facilitating signaling leading to disruption of mitochondria.
 ...
PMID:GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption. 1784 3


1 2 3 4 Next >>