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)

Arsenic trioxide (ATO) is known to have concentration-dependent dual effects on acute promyelocytic leukemia (APL) cells, preferentially inducing apoptosis at relatively high concentrations and promoting partial differentiation at low concentrations. Protein phosphatase 2A (PP2A) has been demonstrated to take part in the differentiation and apoptosis of malignant hematological cells induced by commonly used medicines, such as all-transretinoic acid (ATRA), interferon, arsenic sulfide, etc. However, there are almost no data on the role PP2A plays in ATO-induced APL cell differentiation/apoptosis. In this report, our goal was to show that ATO inhibited the proliferation and induced the apoptosis and differentiation of neuroblastoma NB4 cells. Okadaic acid (OKA), a specific inhibitor of protein phosphatase activity, markedly increased these effects of ATO on cells. To further elucidate the regulation of PP2A during ATO-induced differentiation/apoptosis of NB4 cells, we measured the phosphatase activity and protein expression of PP2A. The activity of PP2A in NB4 cells decreased with increasing concentration of ATO. This decrease of PP2A activity appeared to parallel phenotypic and functional changes of NB4 cells. Western blot analysis showed that the levels of the PP2A structural subunit PP2A-A decreased during the course of ATO-induced differentiation/apoptosis, whereas the expression of the B and C subunits of PP2A was relatively unaltered. In conclusion, the decrease of PP2A activity may be involved in ATO-induced apoptosis and differentiation of APL cells, and this decrease is predicted to be related to the repression of PP2A-A subunit expression.
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PMID:Involvement of protein phosphatase 2A in arsenic trioxide-induced differentiation and apoptosis of NB4 cells. 1885 42

Altered folate homeostasis is associated with many clinical and pathological manifestations in the CNS. Notably, folate-mediated one-carbon metabolism is essential for methyltransferase-dependent cellular methylation reactions. Biogenesis of protein phosphatase 2A (PP2A) holoenzyme containing the regulatory B(alpha) subunit, a major brain tau phosphatase, is controlled by methylation. Here, we show that folate deprivation in neuroblastoma cells induces downregulation of PP2A leucine carboxyl methyltransferase-1 (LCMT-1) expression, resulting in progressive accumulation of newly synthesized demethylated PP2A pools, concomitant loss of B(alpha), and ultimately cell death. These effects are further accentuated by overexpression of PP2A methylesterase (PME-1) but cannot be rescued by PME-1 knockdown. Overexpression of either LCMT-1 or B(alpha) is sufficient to protect cells against the accumulation of demethylated PP2A, increased tau phosphorylation, and cell death induced by folate starvation. Conversely, knockdown of either protein accelerates folate deficiency-evoked cell toxicity. Significantly, mice maintained for 2 months on low-folate or folate-deficient diets have brain-region-specific alterations in metabolites of the methylation pathway. Those are associated with downregulation of LCMT-1, methylated PP2A, and B(alpha) expression and enhanced tau phosphorylation in susceptible brain regions. Our studies provide novel mechanistic insights into the regulation of PP2A methylation and tau. They establish LCMT-1- and B(alpha)-containing PP2A holoenzymes as key mediators of the role of folate in the brain. Our results suggest that counteracting the neuronal loss of LCMT-1 and B(alpha) could be beneficial for all tauopathies and folate-dependent disorders of the CNS.
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PMID:Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. 1898 84

Calcium-dependent cell death occurs in neurodegenerative diseases and ischemic or traumatic brain injury. We analyzed whether thioureylenes can act in a neuroprotective manner by pharmacological suppression of calcium-dependent pathological pathways. In human neuroblastoma (SK-N-SH) cells, thioureylenes (thiopental, carbimazole) inhibited the calcium-dependent neuronal protein phosphatase (PP)-2B, the activation of the proapoptotic transcription factor nuclear factor of activated T-cells, BAD-induced initiation of caspase-3, and poly-(ADP-ribose)-polymerase cleavage. Caspase-3-independent cell death was attenuated by carbimazole and the protein kinase C (PKC) delta inhibitor rottlerin by a PP-2B-independent mechanism. Neuroprotective effects were mediated by the redox-active sulfur of thioureylenes. Furthermore, we observed that the route of calcium mobilization was differentially linked to caspase-dependent or independent cell death and that BAD dephosphorylation did not necessarily induce intrinsic caspase activation. In addition, a new 30- to 35-kDa caspase-3 fragment with an unknown function was identified. In organotypic hippocampal slice cultures, thioureylenes inhibited caspase-3 activation or reduced N-methyl-d-aspartate and kainic acid receptor-mediated cell death that was independent of caspase-3. Because prolonged inhibition of caspase-3 resulted in caspase-independent cellular damage, different types of cell death must be taken under therapeutic consideration. Here we show that thioureylenes in combination with PKCdelta inhibitors might represent a promising therapeutic approach to attenuate neuronal damage.
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PMID:Heterocyclic thioureylenes protect from calcium-dependent neuronal cell death. 1910 61

We recently found protein histidine phosphatase (PHP) in eukaryotes and identified ATP-citrate lyase (ACL) and the beta-subunit of G-proteins as its substrates. The aim of the present study was to get information on the significance of PHP for cellular function and viability. PHP was overexpressed by a viral vector in SH-SY5Y cells, a human neuroblastoma cell line, and in primary cultures of cortical neurons from embryonic (E19) rats. Furthermore, PHP was downregulated by siRNA in SH-SY5Y cells. We could demonstrate that overexpression of PHP decreased the phosphorylation state of ACL. Accordingly, the activity of ACL seemed to be reduced and subsequently, the viability of the cells was diminished. On the other hand, downregulation of PHP did not clearly influence phosphorylation and activity of ACL as well as viability of the cells. The results suggest that an increased activity of PHP impairs cellular function whereas downregulation of PHP does not.
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PMID:Role of protein histidine phosphatase for viability of neuronal cells. 1913 78

Calcineurin (CN) is a Ca(2+)/calmodulin-dependent protein phosphatase expressed at high levels in brain. Many findings have shown that calcineurin plays an important role in tau hyperphosphorylation, which is one of the neuropathologic features in the brains of Alzheimer's disease (AD). Based on the molecular screening model using p-nitrophenyl phosphate (p-NPP) as a substrate for preliminary screening and (32)P-labeled 19-residue phosphopeptide as a specific substrate for final determination, we found that the total ginsenoside extracts from stems and leaves of Panax ginseng (GSL) could enhance the phosphatase activity of purified CN. In the human neuroblastoma cells SY5Y, inhibition of CN by cyclosporine A (CsA) could induce hyperphosphorylation of tau at multiple sites, accompanied with oxidative stress. Pretreatment of the cells with GSL prior to CsA exposure could alleviate CsA-induced CN inhibition and tau hyperphosphorylation to some degree. Further oxidative parameters demonstrated that GSL caused increased SOD activity and content of SH significantly. It is speculated that GSL weakens CsA-induced CN inhibition through the antioxidant mechanisms. Although our results indicate that GSL may have neuroprotective effects on some characteristic features of AD, the chemical compositions of GSL and their potential for affecting the disease mechanism need to be further studied.
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PMID:The neuroprotective effects of ginsenosides on calcineurin activity and tau phosphorylation in SY5Y cells. 1951 26

In a previous paper we reported that the cytoplasmic sequestered p53 in cells of the SK-N-SH neuroblastoma cell line could be induced to translocate to the nucleus by exposure to ionizing radiation. We have extended these studies to determine the fate of p53 in HCT116 colorectal carcinoma cells where constitutive p53 protein resides in the nucleus. A continuous increase in the nuclear p53 protein was observed in irradiated cells beginning 1 h after irradiation that persisted for 8 h. Surprisingly, immunofluorescence microscopy revealed a transient, rapid and sensitive increase in a radiation-induced nuclear dephosphorylated p53 using antibody PAb421, which detects p53 when serine 376 is dephosphorylated. The PAb421 epitope was detectable after exposure to radiation doses as low as 0.5 cGy and was 10 to 20 times more sensitive compared to detection of p53 protein levels. The results are consistent with a radiation-induced, sensitive and rapid dephosphorylation of p53 at serine 376. The rapid increase in the nuclear PAb421 epitope was blocked by the protein serine phosphatase inhibitor calyculin A but was not blocked by the protein synthesis inhibitor cycloheximide, suggesting that serine 376 was dephosphorylated by protein serine phosphatase 1 or 2A acting on pre-existing p53 protein. The data suggest that dephosphorylation of serine 376 on constitutive nuclear p53 is a sensitive and early signaling event in the response of cells to DNA damage induced by ionizing radiation.
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PMID:Transient dephosphorylation of p53 serine 376 as an early response to ionizing radiation. 1958 Apr 79

Protein phosphatase inhibition assay (PPIA), Neuroblastoma cell-based assay (Neuro-2a CBA) and LC-MS/MS analysis revealed for the first time the production of okadaic acid (OA) by a Prorocentrum rhathymum strain. Low amounts of OA were detected by LC-MS/MS analysis. Inhibition of PP2A activity and a weak toxicity to the Neuro-2a CBA were also observed.
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PMID:Evidence of okadaic acid production in a cultured strain of the marine dinoflagellate Prorocentrum rhathymum from Malaysia. 1963 80

The contribution of zinc-mediated neuronal death in the process of both acute and chronic neurodegeneration has been increasingly appreciated. Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN), the major tumor suppressor and key regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, plays a critical role in neuronal death in response to various insults. NEDD4-1-mediated PTEN ubiquitination and subsequent degradation via the ubiquitin proteosomal system have recently been demonstrated to be the important regulatory mechanism for PTEN in several cancer types. We now demonstrate that PTEN is also the key mediator of the PI3K/Akt pathway in the neuronal response to zinc insult. We used primary cortical neurons and neuroblastoma N2a cells to show that zinc treatment results in a reduction of the PTEN protein level in parallel with increased NEDD4-1 gene/protein expression. The reduced PTEN level is associated with an activated PI3K pathway as determined by elevated phosphorylation of both Akt and GSK-3 as well as by the attenuating effect of a specific PI3K inhibitor (wortmannin). The reduction of PTEN can be attributed to increased protein degradation via the ubiquitin proteosomal system, as we show NEDD4-1 to be the major E3 ligase responsible for PTEN ubiquitination in neurons. Moreover, PTEN and NEDD4-1 appear to be able to counter-regulate each other to mediate the neuronal response to zinc. This reciprocal regulation requires the PI3K signaling pathway, suggesting a feedback loop mechanism. This study demonstrates that NEDD4-1-mediated PTEN ubiquitination is crucial in the regulation of PI3K/Akt signaling by PTEN during the neuronal response to zinc, which may represent a common mechanism in neurodegeneration.
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PMID:Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc. 2010 Aug 27

Dual specificity phosphatases are characterised by their ability to dephosphorylate both phosphotyrosine and phosphoserine/threonine residues within the one substrate. The aim of this study was to characterise the phosphatase activity of the atypical dual specificity phosphatase, DUSP26 on MAP kinases, and to determine its expression, regulation and function in cancer cells. Overexpression and knockdown of DUSP26 in epithelial cells and in vitro phosphatase assays were used to demonstrate that, contrary to several published reports, DUSP26 does not act as a dual specificity phosphatase on ERK, JNK or p38 MAPKs. However, overexpression of DUSP26 in MCF10A epithelial cells suppressed colony formation and acinar growth in 3D culture, effects dependent on its phosphatase activity, while knockdown of DUSP26 in HOSE17.1 cells enhanced colony formation and cellular proliferation. DUSP26 mRNA expression was reduced in neuroblastoma, brain and ovarian cancer cell lines. Consistent with epigenetic silencing of DUSP26, expression was enhanced by treatment of cells with 5-aza-2-deoxycitidine and trichostatin A, and a CpG island upstream of the DUSP26 transcriptional start site was variably methylated in cancer cell lines. Together, these results help to clarify confusion in the literature relating to DUSP26 substrate specificity and support recent reports that substrates other than MAPKs are the primary substrates of this phosphatase. In addition, they indicate that DUSP26 may function as a tumour suppressor in particular cancers.
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PMID:DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs. 2034 85

Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP kinase kinase kinase, is activated by several death stimuli and is tightly regulated by several mechanisms such as interactions with regulatory proteins and post-translational modifications. Here, we report that dual-specificity phosphatase 13A (DUSP13A) functions as a novel regulator of ASK1. DUSP13A interacts with the N-terminal domain of ASK1 and induces ASK1-mediated apoptosis through the activation of caspase-3. DUSP13A enhances ASK1 kinase activity and thus its downstream factors. Small interfering RNA (siRNA) analyses show that knock-down of DUSP13A in human neuroblastoma SK-N-SH cells reduces ASK1 kinase activity. The phosphatase activity of DUSP13A is not required for the regulation of ASK1. This regulatory action of DSUP13 on ASK1 activity involves competition with Akt1, a negative regulator of ASK1, for binding to ASK1. Taken together, this study provides novel insights into the role of DUSP13A in the precise regulation of ASK1.
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PMID:Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A. 2035 50


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