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)

Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.
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PMID:Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. 1150 71

p16 regulates the G(1)-S cell cycle transition by inhibiting the cyclin D-cyclin-dependent kinase (CDK)4/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). We examined the possible derangement of the p16-CDK/cyclin D-pRb pathway in 40 primary neuroblastomas including 18 samples in the unfavorable stages (C and D) and 22 in the favorable stages (A, B, and Ds) by PCR, reverse transcription-PCR, Western blot, and immunohistochemistry and correlated the results with clinical outcome. No samples harbored alterations of the p16 gene. Interestingly, the samples in the unfavorable stages exhibited expression of p16 mRNA and protein more frequently than those in the favorable stages [mRNA, 9 of 18 (50%) versus 2 of 22 (9%), P = 0.006; protein, 5 of 16 (31%) versus 0 of 18 (0%), P = 0.013]. Alterations of the downstream components of the pathway were infrequent. pRb was deregulated in the majority of samples investigated [27 of 33 (82%), 24 with hyperphosphorylated pRb and 3 with no pRb protein]. The phosphorylation status of pRb did not correlate with p16 protein expression, suggesting that the elevated p16 protein may not be functioning properly to regulate the pathway. Among patients of all stages, p16 expression was significantly associated with a lower overall survival. There was no overexpression of MDM2, and loss of p14(ARF) expression and p53 mutation were infrequent events. Taken together, these findings suggest that up-regulated p16 expression may represent a unique feature of aggressive neuroblastoma.
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PMID:p16/p14(ARF) cell cycle regulatory pathways in primary neuroblastoma: p16 expression is associated with advanced stage disease. 1170 66

The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment, p53 protein levels increase in the nucleus, leading to the induction of its transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53 (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis. Cytochrome c and caspase-9 function downstream of p53 in mediating the drug-triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome c release and caspase-9 activation. Furthermore, drug-induced cell death can be prevented by expression of a dominant-negative mutant of caspase-9. These findings define a molecular pathway for mediating DNA damaging drug-induced apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells.
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PMID:p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells. 1247 64

Early studies of p53 in neuroblastoma reported infrequent mutations in tumours and cell lines. Cytoplasmic sequestration was later proposed as an alternative mechanism of inactivation, but many studies have since reported an intact p53 pathway in neuroblastoma cell lines, as detected by nuclear p53 accumulation after DNA damage, intact DNA binding, transcriptional activation of target genes and the induction of apoptosis. In some MYCN amplified cell lines however, an irradiation induced G(1) arrest does not occur, despite the presence of normal p53. Neuroblastoma usually responds to chemotherapy but frequently relapses, and there is evidence from tumours, and cell lines that p53 inactivation via mutation or MDM2 amplification occurs at relapse and is sometimes associated with multidrug resistance. If p53 inactivation occurs frequently in relapsed tumours it may be appropriate to include p53 independent therapies in the initial management of high-risk neuroblastoma.
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PMID:The p53 pathway and its inactivation in neuroblastoma. 1288 Sep 66

Polo-like kinase 1 (Plk1) has an important role in the regulation of M phase of the cell cycle. In addition to its cell cycle-regulatory function, Plk1 has a potential role in tumorigenesis. Here we found for the first time that Plk1 physically binds to the tumor suppressor p53 in mammalian cultured cells, and inhibits its transactivation activity as well as its pro-apoptotic function. During the cisplatin-induced apoptosis in human neuroblastoma SH-SY5Y cells, the expression level of Plk1 was significantly decreased both at mRNA and protein levels, whereas cisplatin treatment caused a remarkable stabilization of p53. Systematic immunoprecipitation analyses using a series of deletion mutants of p53 revealed that a sequence-specific DNA-binding region of p53 is required and sufficient for the physical interaction with Plk1. The ectopically overexpressed Plk1 was co-localized with the endogenous p53 in mammalian cell nucleus, as shown by confocal laser microscopy. Expression of exogenous Plk1 and p53 in p53-deficient lung carcinoma H1299 cells greatly decreased the p53-mediated transcription from the p53-responsive p21(WAF1), MDM2, and BAX promoters, whereas the kinase-deficient mutant form of Plk1 failed to reduce the transcriptional activity of p53. Consistent with the luciferase reporter analysis, Plk1 had an ability to block the p53-dependent induction of the endogenous p21(WAF1). In addition, Plk1 inhibited the pro-apoptotic function of p53 in H1299 cells. Intriguingly, Plk1-mediated repression of p53 was attenuated with ATM. Thus, our present findings strongly suggest that p53 is a critical target of Plk1, and its function is abrogated through the physical interaction with Plk1.
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PMID:Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. 1502 21

One hallmark of Ewing's sarcoma/peripheral neuroectodermal tumors is the presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation program of neuroblastomas to Ewing's sarcoma/peripheral neuroectodermal tumors. Here we examined the status of cytoplasmically sequestered wt-p53 in neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a punctate-pattern of cytoplasmic sequestration to increased nuclear localization. Western blot analysis revealed that PARC was down-regulated in one neuroblastoma cell line but not expressed in the second. Therefore, decreased PARC expression could not fully account for relieving p53 sequestration in the neuroblastoma tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked increases in p53 protein expression without transcriptional up-regulation. Interestingly, p53 was primarily phosphorylated, without activation of its downstream target p21(WAF1). Western blot analysis revealed that whereas MDM2 gene expression does not change, p14(ARF), a negative protein regulator of MDM2, increases. These observations suggest that the downstream p53 pathway may be inactivated as a result of abnormal p53. We also found that p53 has an extended half-life in the neuroblastoma-Ews/Fli-1 infectants despite the retention of a wild-type sequence in neuroblastoma-Ews/Fli-1 infectant cell lines. We then tested the p53 response pathway and observed that the neuroblastoma parent cells responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants did not. These results suggest that Ews/Fli-1 can directly abrogate the p53 pathway to promote tumorigenesis. These studies also provide additional insight into the relationship among the p53 pathway proteins.
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PMID:The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines. 1549 48

The MYCN oncogene is the major negative prognostic marker in neuroblastoma with important roles in both the pathogenesis and clinical behavior of this aggressive malignancy. MYC oncogenes activate both proliferative and apoptotic cellular pathways and, accordingly, inhibition of p53-mediated apoptosis is a prerequisite for MYC-driven tumorigenesis. To identify novel transcriptional targets mediating the MYCN-dependent phenotype, we screened a MYCN-amplified neuroblastoma cell line by using chromatin immunoprecipitation (ChIP) cloning. We identified the essential p53 inhibitor and protooncogene MDM2 as a putative target. MDM2 has multiple p53-independent functions modulating cell cycle and transcriptional events. Standard ChIP with MYCN antibodies established the binding of MYCN to a consensus E-box within the human MDM2 promoter. Oligonucleotide pull-down assays further established the capacity of MYCN to bind to this promoter region, confirming the ChIP results. Luciferase reporter assays confirmed the E-box-specific, MYCN-dependent regulation of the MDM2 promoter in MYCN-inducible neuroblastoma cell lines. Real-time quantitative PCR and Western blot analysis demonstrated a rapid increase in endogenous MDM2 mRNA and MDM2 protein upon induction of MYCN. Targeted inhibition of MYCN in a MYCN-amplified neuroblastoma cell line resulted in decreased MDM2 expression levels with concomitant stabilization of p53 and induction of apoptosis. Our finding that MYCN directly modulates baseline MDM2 levels suggests a mechanism contributing to the pathogenesis of neuroblastoma and other MYC-driven malignancies through inhibition of MYC-stimulated apoptosis.
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PMID:The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. 1564 44

p73, a newly identified member of p53 family, locates at human chromosome 1p36.2-3, a region which is frequently deleted in a wide variety of human tumors including neuroblastoma. p73 is induced to be accumulated in response to a subset of DNA damaging agents such as cisplatin, and thereby promoting G1/S cell cycle arrest and/or apoptosis. Since the expression levels of p73 are kept extremely low under normal conditions, stabilization of p73 is critical for its effects on cell growth inhibition and apoptosis. Indeed, p73 is induced at protein level in SH-SY5Y neuroblastoma cells exposed to cisplatin. Several lines of evidence indicate that stress-induced post-translational modifications of p73 such as phosphorylation and acetylation lead to a marked extension of its half-life. p73 stability is regulated at least in part by proteasome-dependent degradation pathway, however, MDM2 which mediates ubiquitination and subsequent degradation of p53 by the 26S proteasome, does not promote the proteolytic degradation of p73, implying that the protein stability of p73 is regulated through a pathway distinct from that of p53. Although little is known about the regulation of p73 turnover, we are now beginning to understand the regulatory mechanisms by which p73 is induced to be stabilized in response to apoptotic stimuli, and exerts its pro-apoptotic activity. In this review, we discuss about the cellular proteins implicated in the stability control of p73.
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PMID:Functional implication of p73 protein stability in neuronal cell survival and death. 1590 64

The MYCN oncogene plays an important role in the pathogenesis of neuroblastoma. It is amplified in more than 30% of high-risk cases and over expression induces neuroblastoma in transgenic mice. MYCN amplification/overexpression is found in many types of cancers including neuroblastoma, medulloblastoma and other aggressive tumors of neuroectodermal origin as well as in rhadomyosarcoma and small cell lung cancers. MYCN exerts its oncogenic effects through transcriptional regulation of numerous target genes. We have recently characterized the p53 inhibitor MDM2 (HDM2) as one such target in MYCN amplified neuroblastoma cell lines. Conditional expression of MYCN yields elevated MDM2 mRNA and protein. MYCN inhibition leads to diminished MDM2, stabilized p53 and apoptosis. As the primary negative regulator of p53, MDM2 is critically regulated in normal cells to ensure adequate p53 activity in response to damage or stress. Additionally, MDM2 regulates many p53 independent processes pertinent to oncogenesis. We propose that increased MDM2 levels downstream of MYCN are tumorigenic secondary to disruption of multiple p53 dependent and independent mechanisms controlling genomic stability, apoptopsis and cell cycle progression. Further research into the MYCN/MDM2 regulated pathways will provide insight into the pathogenesis of MYCN-driven tumors and provide targets for novel therapeutic interventions.
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PMID:MDM2 as a critical effector of the MYCN oncogene in tumorigenesis. 1591 61

MYCN amplification is associated with an exceptionally poor prognosis in neuroblastoma. Furthermore, the crucial effectors of MYCN responsible for this aggressive subset of neuroblastoma await characterization. A critical negative regulator of the p53 tumor suppressor, MDM2, has been recently characterized in neuroblastoma cell lines as a transcriptional target of MYCN. Targeted inhibition of MYCN results in reduced MDM2 expression levels, with concomitant stabilization of p53 and stimulation of apoptosis in MYCN amplified neuroblastoma cell lines. These data suggest the possibility that MYCN-driven expression of MDM2 might play a role in counterbalancing the p53-dependent apoptotic pathways concurrently stimulated by over expression of MYC proteins. Mouse models of lymphoma have demonstrated that MDM2 expression, with decreased p53 activity, is critical for complete MYCC driven tumorigenesis. Our data suggest that a similar situation may apply for MYCN in neuroblastoma. Strategies for pharmacologic and genetic inhibition of MDM2 may prove to be an important new therapeutic approach in neuroblastoma.
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PMID:MDM2 as MYCN transcriptional target: implications for neuroblastoma pathogenesis. 1592 64


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