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)

The thyroid hormone (triiodothyronine, T3) is essential for normal brain maturation. To determine the mechanisms by which T3 controls neuronal proliferation and differentiation, we have analyzed the effect of this hormone on the expression and activity of cell cycle-regulating molecules in neuroblastoma N2a-beta cells that overexpress the beta1 isoform of the T3 receptor. Our results show that incubation of N2a-beta cells with T3 leads to a rapid down-regulation of the c-myc gene and to a decrease of cyclin D1 levels. T3 also causes a strong and sustained increase of the levels of the cyclin kinase inhibitor p27(Kip1). This increase is secondary, to the augmented levels of p27(Kip1) transcripts as well as to stabilization of the p27(Kip1) protein. The increased levels of p27(Kip1) lead to a significant increase in the amount of p27(Kip1) associated with cyclin-dependent kinase 2 (CDK2), and to a marked inhibition of the kinase activity of the cyclin.CDK2 complexes. As a consequence, the retinoblastoma protein (pRb) and the retinoblastoma protein-related protein p130 are hypophosphorylated in T3-treated N2a-beta cells. This study shows for the first time that T3-mediated growth arrest and neuronal differentiation are associated with an increase in the levels of a cyclin kinase inhibitor, which does not allow the inactivation of retinoblastoma proteins required for progression through the restriction point in the cell cycle.
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PMID:The cyclin-dependent kinase inhibitor p27(Kip1) is involved in thyroid hormone-mediated neuronal differentiation. 998 48

The activities of the mammalian G1 cyclins, cyclin D and cyclin E, during cell cycle progression (G1/S) are believed to be regulated by cell attachment and the presence of growth factors. In order to study the importance of cell attachment and concomitant integrin signaling on the expression of G1 cyclins during the natural adhesion process from mitosis to interphase, protein expression was monitored in cells that were synchronized by mitotic shake off. Here we show that in Chinese hamster ovary (CHO) and neuroblastoma (N2A) cells, expression of cyclin E at the M/G1 transition is regulated by both growth factors and cell attachment, while expression of cyclin D seems to be entirely dependent on the presence of serum. Expression of cyclin E appears to be correlated with the phosphorylation of the retinoblastoma protein, suggesting a link with the activity of the cyclin D/cdk4 complex. Expression of the cdk inhibitors p21(cip1/Waf1) and p27(Kip1) is not changed upon serum depletion or detachment of cells during early G1, suggesting no direct role for these CKIs in the regulation of cyclin activity. Although inhibition of cyclin E/cdk2 kinase activity has been reported previously, this is the first time that cyclin E expression is shown to be dependent on cell attachment.
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PMID:Integrin signaling at the M/G1 transition induces expression of cyclin E. 1058 65

The sensitive-to-apoptosis gene (SAG) was initially identified as a redox-inducible, apoptosis-protective protein and subsequently found to be the second family member of regulator of cullins (ROC)/RING box protein (Rbx)/Hrt, which acts as a component of E3 ubiquitin ligase. We report here that SAG promoted cell growth under serum starvation. Microinjection of SAG mRNA into quiescent NIH/3T3 cells induced S-phase entry as determined by [(3)H]-thymidine incorporation. Likewise, overexpression of SAG by either adenovirus infection of immortalized human epidermal keratinocytes (Rhek-1) or DNA transfection of SY5Y human neuroblastoma cells induced cell proliferation under serum starvation. Because cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57, are degraded through the ubiquitin pathway, we tested whether SAG-induced cell growth is associated with CKI degradation. Although there was no significant difference in the levels of p21 and p57 between the vector controls and SAG-overexpressing cells, serum starvation induced 10- to 18-fold accumulation of p27 in control Rhek-1 cells. Accumulation of p27 was remarkably inhibited (only 2 to 5-fold) in SAG-infected cells. Inhibition of p27 accumulation was also observed in stably SAG-overexpressing SY5Y cells. Significantly, SAG-associated inhibition of p27 accumulation was largely abolished by the treatment with a proteasome inhibitor. In vivo binding of SAG and Skp2, an F-box protein that promotes p27 ubiquitination, was detected, and the binding was enhanced in SAG-overexpressing cells grown under serum starvation. Thus, SAG-induced growth with serum withdrawal appears to be associated with SAG-mediated p27 degradation. Mol. Carcinog. 30:37-46, 2001.
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PMID:Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. 1125 62

Amplification of the MYCN gene is significantly associated with an unfavorable prognosis and rapid progression in human neuroblastoma tumors. One potential mechanism by which MYCN may cause these effects is by deregulating cell proliferation. Tissue culture experiments support a model in which MYC genes stimulate cell cycle progression by antagonizing the function of the cell cycle inhibitor p27(kip1). In culture, activation of MYC induces both sequestration of p27(kip1) by cyclin D complexes and its subsequent proteolytic degradation. We have tested whether this model applies to human neuroblastoma in a retrospective study of 100 primary tumor biopsy samples from neuroblastoma patients with a documented follow-up. Consistent with this hypothesis, MYCN-amplified tumors express high levels of both cyclin A and proliferating cell nuclear antigen, 2 marker proteins of cell proliferation. Further, expression levels of p27(kip1) are of prognostic significance in human neuroblastoma patients. Similar to tissue culture systems, p27(kip1) is sequestered by cyclin D complexes in a subset of human neuroblastoma samples. Surprisingly, however, expression levels of p27(kip1) are prognostic independent of MYCN amplification, and tumors that have an amplified MYCN gene do not express elevated levels of D-type cyclins or contain significantly lower levels of p27(kip1). Our data do not support a model in which regulation of p27(kip1) function is an important mechanism by which amplified MYCN deregulates cell proliferation in neuroblastoma.
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PMID:Expression of P27(KIP1) is prognostic and independent of MYCN amplification in human neuroblastoma. 1130 51

The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that overexpress the beta 1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27(Kip1) are found in T3-treated cells. The increased levels of p27(Kip1) lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-beta cells, and progression through the restriction point in the cell cycle is blocked.
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PMID:Cell cycle control by the thyroid hormone in neuroblastoma cells. 1250 6

Poor prognosis neuroblastoma (NB) tumors are marked by amplification and overexpression of N-myc. Retinoic acid (RA) decreases N-myc levels and induces cell cycle arrest in vitro and increases event-free survival in advanced stage NB patients. In this study, we investigated the mechanism(s) by which RA regulates cell cycle and how N-myc affects NB cell cycle progression. Constitutive N-myc overexpression stimulates increases in cyclin E-dependent kinase activity and decreases in p27 resulting in increased DNA synthesis. N-myc regulates p27 levels through an increase in targeting of p27 to the proteasome via cyclin E kinase-dependent phosphorylation of p27 and its ubiquitination. N-myc also stimulates an increase in proteasome activity. In RA-treated cells in which N-myc levels decline as p27 levels increase, degradation of p27 is also decreased. However, RA does not affect the activity of proteasome. The decrease in the degradation of p27 in RA-treated cells is due in part to a decrease in the N-myc stimulated phosphorylation of p27. However, RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated. Thus, RA induces both N-myc-dependent and -independent mechanisms to minimize the degradation of p27 and arrest NB cell growth.
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PMID:Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2. 1270 Jun 51

Neuronal differentiation implies morphological and biochemical changes to generate a specialized neuron. N2A neuroblastoma cells can be promoted to undergo differentiation associated to neurites outgrowth, a process linked to the arrest of cell division. Using N2A cells as a model, we investigated the detailed molecular aspects on the involvement of p27 in dibutyryl cAMP-induced neuronal differentiation. In the undifferentiated N2A phenotype, an unusually high level of accumulated p27 protein mass was evidenced. Data suggest that in proliferating cells, p27 could be sequestered by direct interaction with cyclin D1, thus preventing its inhibitory action on cell cycle Cdks. Studies also indicate that p27 is functionally active and that its loss of action on Cdks in proliferating cells is due to its strong association with cyclin D1. Therefore, when cell differentiation is triggered, the action of p27 on Cdks seems to depend on both p27 and cyclin D1 degradation during the early steps of differentiation followed by late events of re-synthesis of active p27. In this context, an overexpression of p27 after N2A transfection with a mouse p27 clone induces the outgrowth of neurites associated with a decrease in cyclin D1 expression. On the other hand, treatment of N2A undifferentiated cells with c-myc antisense oligonucleotides led to a decrease in p27 and cyclin D1 levels, similar events as those in early stages of cell differentiation. Studies suggest that blockage in c-myc expression triggers early events in neuronal differentiation. These studies are of the utmost importance to elucidate regulatory mechanisms of molecules that play a critical role in the transition from a proliferating phenotype to differentiated cells.
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PMID:Regulation of p27 in the process of neuroblastoma N2A differentiation. 1276 87

Proteasome activity is essential during cAMP-induced terminal differentiation of a murine neuroblastoma cell line (NBP2). However, the mechanisms through which proteasome affects NBP2 differentiation have not been characterized. We hypothesized that proteasome is required to implement the differentiation-mediated effects on cell cycle, and its partial inhibition during differentiation may have adverse consequences. Here we show that partial inhibition of proteasome during cAMP-induced differentiation of NBP2 cells causes apoptosis. Whereas differentiation induced growth arrest at G1 phase, partial proteasome inhibition during differentiation resulted in the accumulation of cells at G2M phase. Cell cycle data correlated with the level of cyclin-dependent kinase inhibitors p21WAF and p27Kip1, and cyclin A. While the level of p21 and p27 increased, the level of cyclin A decreased upon differentiation. In contrast, cells treated with proteasome inhibitor in the presence of cAMP-inducing agents showed increased levels of p21 and cyclin A early in the course of differentiation. However, the level of p21 and p27, but not cyclin A, decreased later during concomitant differentiation and partial proteasome inhibition when cells were undergoing apoptosis. Our data suggest that differentiation-mediated growth arrest is dependent on the temporal activity of cell cycle proteins. Partial inhibition of proteasome interferes with differentiation events partly by stabilizing cell cycle proteins and this triggers apoptosis. Thus, differentiating drugs combined with partial proteasome inhibition may impart higher therapeutic efficacy than differentiating agents alone for the treatment of neuroblastoma tumors.
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PMID:Concomitant differentiation and partial proteasome inhibition trigger apoptosis in neuroblastoma cells. 1281 50

In neuroblastoma (NB), expression of the TrkA receptor is correlated with good prognosis while N-myc amplification is correlated with poor prognosis. Decreased N-myc levels are key to controlling growth and inducing differentiation in NB cells. In this report, we detail mechanisms by which nerve growth factor (NGF) decreases N-myc levels in TrkA-transfected NB cells and its effect on NB cell proliferation. NGF induced a decrease in N-myc mRNA within 1 h of treatment that occurred in the presence of cycloheximide. The stability of N-myc mRNA was not affected by NGF, indicating a transcriptional control of N-myc mRNA by NGF. NGF but not brain-derived neurotrophic factor (BDNF) decreased N-myc levels demonstrating that p75 alone was not involved. The NGF-induced decrease in N-myc expression was blocked by the Trk tyrosine kinase (TK) antagonist K252a indicating that signals transduced by Trk TK downstream targets were involved. Pharmacologic inhibitors implicated the mitogen-activated protein kinase (MAPK) path. This was supported by the finding that expression of a constitutively activated component of the MAPK path, MAPK kinase (MEK), decreased N-myc levels. Alterations in the level of N-myc are known to alter NB cell cycle progression by affecting the levels of E2Fs and p27(kip1). Consistent with these findings, NGF decreased NB cell number and decreased cyclin E-dependent kinase activity via an increase in p27(kip1). Thus, our results indicate that the MAP kinase is selectively involved in the NGF-induced N-myc downregulation through a transcriptional mechanism. Furthermore, NGF affects the time required for 15N TrkA cells to complete a replication cycle by decreasing N-myc, E2Fs, cyclin E kinase activity and increasing p27(kip1) binding to cyclin E kinase.
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PMID:NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number. 1469 55

Mycophenolic acid (MPA) specifically inhibits inosine-5'-monophosphate dehydrogenase, the first committed step toward GMP biosynthesis. In its morpholinoethyl ester pro-drug form it is one of the most promising immunosuppressive drugs recently developed. The aim of the present study was to investigate the in vitro effects of MPA, at concentrations readily attainable during immunosuppressive therapy, on 3 human neuroblastoma cell lines (LAN5, SHEP and IMR32). Mycophenolic acid (0.1-10 microM) caused a decrease of intracellular levels of guanine nucleotides, a G(1) arrest and a time- and dose-dependent death by apoptosis. These effects, associated with an up-regulation of p53, p21 and bax, a shuttling of p53 protein into the nucleus and a down-regulation of bcl-2, survivin and p27 protein, were reversed by the simultaneous addition of guanine or guanosine and were more evident using nondialysed serum containing hypoxanthine. These results suggest that in neuroblastoma cell lines clinically attainable concentrations of mycophenolic acid deplete guanine nucleotide pools triggering G(1) arrest and apoptosis through p53-mediated pathways, indicating a potential role of its morpholinoethyl ester pro-drug in the management of patients with neuroectodermal tumors.
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PMID:Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines. 1535 52


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