Neoplastic transformation by the human gene N-myc.

Small, Michael B.; Hay, Nissim; Schwab, Manfred; Bishop, J. Michael

doi:10.1128/mcb.7.5.1638

Cited by 115 publications

(76 citation statements)

References 40 publications

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“…N-myc is a member of the myc family of proto-oncogenes involved in initiation and progression of tumors (16,17). As shown in previous studies, human N-myc expressed at sufficient levels could induce morphological transformation, anchorage independence, and tumorigenicity in rodent fibroblast cell line Rat-1 (18). Mouse aML hepatocytes infected with a retroviral vector overexpressing the N-myc gene displayed a higher proliferation rate than parental aML cells at normal serum concentration, but it was unable to arrest growth in low serum and was more prone to cell death on serum deprivation (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…First-strand cDNA was synthesized as follows: 1 h at 42 8C with 100 U MMLV reverse transcriptase (Promega), 15 U Rnasin (Promega), 500 lM each deoxy-nucleotidetriphosphate (dNTP), 0.5 lg oligo(dT) 18 , and 2 lg total RNA in a final volume 25 lL, then 5 min at 95 8C. The full-length SMYD3 gene was amplified by PCR using the cDNA and the following primer pair: 5 0 -AAGGAATTCACGATGCGATGCTCTCAGTG-3 0 (forward) and 5 0 -TGCGGATCCTCAGGATGCTCTGATGTTG-3 0 (reverse).…”

Section: Construction Of Smyd3 Expression Vectormentioning

confidence: 99%

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Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells

Luo

Guo

et al. 2009

IUBMB Life

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SummaryThe SET and MYND domain-containing protein 3 (SMYD3) gene was found to encode a novel histone methyltransferase involved in human cancer cells. It could specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including of several oncogenes (e.g., N-Myc, CrkL, Wnt10b, RIZ, and hTERT) and genes involved in the control of cell cycle (e.g., Cyclin G1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11, and PIK3CB). To determine the effects of SMYD3 overexpression on cell transformation, serum dependence and apoptosis sensitivity, we expressed SMYD3 in NIH3T3 cells, and these cells showed several transformed phenotypes as demonstrated by foci formation and colony growth in soft agar. Besides, these transfectants also showed increased serum dependence and depression of sensitivity to apoptosis induced by dexamethasone. These findings lend further understanding to the role of SMYD3 in the genesis of human cancers and might throw light on the development of novel therapeutic approaches to human cancers.2009 IUBMB IUBMB Life, 61(6): 679-684, 2009

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Section: Discussionmentioning

confidence: 99%

Section: Construction Of Smyd3 Expression Vectormentioning

confidence: 99%

Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells

Luo

Guo

et al. 2009

IUBMB Life

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“…54 The oncogenic effects of MYCN overexpression have been convincingly established in a variety of model systems. Enhanced expression of MYCN elicits neoplastic transformation of mammalian cells, 55,56 induces autocrine growth factor activity and increases proliferative potential, 57 accelerates cell-cycle progression, 58 enhances tumor cell motility and invasiveness, 59 evokes genomic instability through disruption of the regulation of centrosome replication, 60,61 diminishes expression of angiogenesis Figure 2 Schematic diagram of p53 stabilization and activation by p14 ARF . The p14 ARF protein is predominantly localized to the nucleolus, in which it is stabilized by binding to nucleophosmin within maturing pre-ribosomal particles, pointing to a function in the regulation of ribosome biogenesis.…”

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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“…The neural origin of some SCLCs may serve to explain why some of the genes mutated in this type of lung cancer are also altered in other neuralrelated tumors. Such is the case of N-MYC and RB1 , which are commonly altered in neuroblastomas and retinoblastomas, respectively ( 7,8 ).…”

Section: Introductionmentioning

confidence: 99%

MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1

et al. 2014

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Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplifi cation of L-MYC , N-MYC , and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specifi c inactivation of the MYC-associated factor X gene, MAX , in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1 , the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifi cally in MAX-defi cient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. SIGNIFICANCE:We discovered that the MYC-associated factor X gene, MAX , is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-defi cient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-defi cient tumors. Cancer Discov; 4(3);[292][293][294][295][296][297][298][299][300][301][302][303]

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Neoplastic transformation by the human gene N-myc.

Cited by 115 publications

References 40 publications

Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells

Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells

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

MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1

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