N-Myc overexpression leads to decreased β1 integrin expression and increased apoptosis in human neuroblastoma cells

Golen, Cynthia M. van; Soules, Mary E.; Grauman, Alyssa; Feldman, Eva L.

doi:10.1038/sj.onc.1206362

Cited by 41 publications

(33 citation statements)

References 63 publications

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“…In addition, neuroblastoma cell lines without MYCN amplification, which express little or no MYCN, have often been used to assess the biological effect of high-level MYCN expression in neuroblastoma by its ectopic expression via transfection. This operation sensitizes these neuroblastoma cells to apoptosis with or without additional stimuli (45)(46)(47)(48), and these results are even thought to be paradoxical (48). However, results of this study are in fact consistent with these previous experimental data.…”

Section: Discussionsupporting

confidence: 40%

TheMYCNEnigma: Significance ofMYCNExpression in Neuroblastoma

et al. 2006

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MYCN amplification strongly predicts adverse outcome of neuroblastoma. However, the significance of MYCN expression in the clinical and biological behavior of neuroblastoma has been unclear. To address this question, we first examined the expression of MYCN in combination with TrkA (a favorable prognostic indicator of neuroblastoma) in 91 primary neuroblastoma by quantitative reverse transcription-PCR and investigated the relationship among patient survival, MYCN, and TrkA expressions. Three subsets of neuroblastoma were defined based on MYCN and TrkA expression. Neuroblastoma expressing the highest level of MYCN but little TrkA were MYCN-amplified cases, which had a 5-year survival of 9.3%. Interestingly, MYCN and TrkA expression showed a linear correlation (r = 0.5664, P < 0.00005) in neuroblastoma lacking MYCN amplification, and the 5-year survival of neuroblastoma patients with low MYCN and low TrkA expressions was 63.7%, whereas those with high expression of both had a 5-year survival of 88.1% (P < 0.00005). This nonlinear distribution of disease outcome relative to MYCN expression in neuroblastoma explains why MYCN expression is not predictive of neuroblastoma disease outcome by dichotomous division of the neuroblastoma cohort. However, highlevel MYCN expression is associated with favorable outcome in neuroblastoma lacking MYCN amplification. Furthermore, forced expression of MYCN significantly suppresses growth of neuroblastoma cells lacking MYCN amplification by inducing apoptosis and enhancing favorable neuroblastoma gene expression. Collectively, these data suggest that highlevel MYCN expression in neuroblastoma lacking MYCN amplification results in a benign phenotype. Thus, the high MYCN expression confers the opposite biological consequence in neuroblastoma, depending on whether or not MYCN is amplified. (Cancer Res 2006; 66(5): 2826-33)

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Section: Discussionsupporting

confidence: 40%

TheMYCNEnigma: Significance ofMYCNExpression in Neuroblastoma

et al. 2006

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“…64 Direct evidence for a causative role of MYCN amplification in the pathogenesis of neuroblastoma is derived from the observation that transgenic mice with targeted expression of MYCN in normal neuroblasts develop tumors with a phenotype very similar to human neuroblastoma. 65 However, aberrant MYCN expression also potently sensitizes neuroblastoma cells to drug-and stress-induced apoptosis, [66][67][68][69] and, therefore, needs to be accompanied by a collateral impairment of the cell death program to provide a selective advantage for the tumor. This counterbalance to the intrinsic apoptosis-sensitizing effect of MYCN may be delivered by an increased activity of MDM2.…”

Section: Transactivation Of Mdm2 Expression By Mycnmentioning

confidence: 99%

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

et al. 2009

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A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14 ARF -MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. The p53 tumor surveillance network constitutes the core defense mechanism of the cell against loss of genomic integrity and malignant transformation. Evasion of p53 activity is, therefore, a prerequisite for tumor cells to survive and thrive, and this is attainable either through mutation of the TP53 gene or through defects in the molecular components that govern or execute the various aspects of the p53 response. Elucidation of the mechanisms by which tumor cells override the p53-orchestrated failsafe program is not only important to gain insight into the ontogenesis of a tumor, but may also point to preferable modes of therapeutic intervention.A striking feature of the childhood cancer neuroblastoma is the low frequency (o2%) of TP53 mutations at diagnosis. 1 There is considerable evidence that TP53 mutations may be acquired during chemotherapy and malignant progression of neuroblastoma. 1-4 Accordingly, an increased frequency of TP53 mutations is observed in multidrug-resistant neuroblastoma cell lines and in neuroblastoma cell lines established at relapse, but even in this context, the majority of cell lines remain characterized by a wild-type TP53 gene. 5,6 Furthermore, many studies indicate that the p53 signal transduction pathway is intrinsically intact in neuroblastoma, 1,4,7-9 suggesting that circumvention of the p53 barrier in this tumor entity relies primarily on an inappropriately increased activity of inhibitors of p53 signaling or, alternatively, on a loss of positive regulators of p53 activity. This review summarizes our current understanding of the mechanisms by which neuroblastoma cells escape from p53-mediated tumor surveillance and positions deregulation of the p14 ARF -MDM2-p53 axis as a central switch for p53 inactivation in neuroblastoma.The p14 ARF -MDM2-p53 Axis and Lesions at the MDM2 and CDKN2A (p16 INK4a /p14 ARF ) Loci in NeuroblastomaThe MDM2 oncoprotein, a human homolog of the 'mouse double minute 2' gene product that was originally identified in a spontaneously transformed mouse cell line with double minute chromosomes, 10 is a critical negative regulator of p53 stability and activity. It has been well established that p53 and MDM2 mutually control their cellular levels and form a tight autoregulatory...

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“…Paradoxically, N-myc overexpression leads not only to an increased tumorigenic phenotype of neuroblastoma cells but also to an increased sensitivity to drug-induced apoptosis (Fulda et al 1999). Furthermore, N-myc overexpression causes increased serum-withdrawal-induced apoptosis in human neuroblastoma cells (van Golen et al 2003). Overexpression of nuclear N-myc in cells that are not scheduled for cell division may lead to apoptotic death (for reviews, see Evan and Vousden 2001;Hogarty 2003).…”

Section: N-myc and The Control Of Neuronal Birth Numbers In The Sensomentioning

confidence: 98%

Increased progenitor proliferation and apoptotic cell death in the sensory lineage of mice overexpressing N-myc

2005

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N-myc, a member of the myc family of bHLH transcription factors, is expressed mainly in the nervous system, including derivatives of neural crest cells in the periphery during development, such as the sensory dorsal root ganglion (DRG). Previous studies suggest that N-myc is involved in the proliferation of progenitor cells in the sensory lineage. To address the role of N-myc in the development of peripheral sensory neurons, we have overexpressed N-myc in sensory progenitor cells. The overexpression of N-myc did not significantly affect the number of multipotent neural crest cells or glial differentiation but caused a brief and marked increase of both proliferation and apoptosis in the DRG at embryonic day 11 (E11), thus coinciding with the stage of cell-cycle exit. At E17, the total number of cells in the lumbar DRG of mice with forced expression of N-myc was significantly reduced compared with that in wild-type mice. Among the different DRG subpopulations examined, the number of parvalbumin-positive neurons representing large-diameter proprioceptive neurons increased significantly. Our results indicate that forced expression of N-myc in the sensory lineage leads to unscheduled cell-cycle re-entry and excessive apoptosis and show that N-myc can affect the composition of different functional subtypes of sensory neurons in the DRG.

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N-Myc overexpression leads to decreased β1 integrin expression and increased apoptosis in human neuroblastoma cells

Cited by 41 publications

References 63 publications

TheMYCNEnigma: Significance ofMYCNExpression in Neuroblastoma

TheMYCNEnigma: Significance ofMYCNExpression in Neuroblastoma

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

Increased progenitor proliferation and apoptotic cell death in the sensory lineage of mice overexpressing N-myc

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