E2F Proteins Regulate MYCN Expression in Neuroblastomas

Strieder, Verena; Lutz, W

doi:10.1074/jbc.m207596200

Cited by 63 publications

(81 citation statements)

References 48 publications

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“…The transcription factors known to regulate Bmi1 expression are sonic hedgehogactivated Gli1 protein (Leung et al, 2004), E2F family members (Nowak et al, 2006), zinc-finger transcription factor SALL4 (Yang J et al, 2007) and c-Myc (Guney et al, 2006). As E2F1 regulates NB tumorigenesis through direct binding to MYCN promoter and its activation, E2F may regulate NB cells using complicated MYCN, MYCN/Bmi1 and Bmi1 regulation mechanisms (Strieder and Lutz, 2003;Kramps et al, 2004). Abbreviation: NB, neuroblastoma.…”

Section: Regulation Of Bmi1 Gene Transcriptionmentioning

confidence: 99%

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

et al. 2010

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Recent advances in neuroblastoma (NB) research addressed that epigenetic alterations such as hypermethylation of promoter sequences, with consequent silencing of tumor-suppressor genes, can have significant roles in the tumorigenesis of NB. However, the exact role of epigenetic alterations, except for DNA hypermethylation, remains to be elucidated in NB research. In this paper, we clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. Mutation introduction into an MYCN binding site in the Bmi1 promoter suggests that MYCN has more important roles in the transcription of Bmi1 than E2F-related Bmi1 regulation. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bb and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bb and TSLC1 are direct targets of Bmi1 in NB cells. These findings suggest that MYCN induces Bmi1 expression, resulting in the repression of tumor suppressors through Polycomb group genemediated epigenetic chromosome modification. NB cell proliferation and differentiation seem to be partially dependent on the MYCN/Bmi1/tumor-suppressor pathways.

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Section: Regulation Of Bmi1 Gene Transcriptionmentioning

confidence: 99%

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

et al. 2010

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“…Chromatin Immunoprecipitation Assay-The protocol for chromatin immunoprecipitation and the primers used have been described (14). PCR products were either visualized on an agarose gel or directly quantified on an ABI7000 using SYBR Green.…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that E2F-1 activates the MYCN promoter in neuroblastoma cells (14). Co-expression of either Sp1 or the long isoform of Sp3 with limiting amounts of E2F-1 resulted in synergistic activation of the MYCN promoter (Fig.…”

Section: Sp1 and Sp3 Activate The Mycn Promoter And Synergize With E2mentioning

confidence: 99%

“…Toward this goal, we have recently identified the activating members of the E2F family of transcription factors (E2F-1, E2F-2, and E2F-3) as regulators of MYCN expression in neuroblastomas (14). E2F proteins are important regulators of cell-cycle progression, and their activity is negatively controlled by the p16/Rb pathway, which is inactivated in the majority of human cancers (for a review, see Refs.…”

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confidence: 99%

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E2F and Sp1/Sp3 Synergize but Are Not Sufficient to Activate the MYCN Gene in Neuroblastomas

Kramps

Strieder

Sapetschnig

et al. 2004

Journal of Biological Chemistry

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The transcription factors encoded by the MYC genes control diverse tumorigenesis-relevant processes such as cell-cycle progression, growth factor dependence, and response to anti-mitogenic signals (for a review, see Refs. 1 and 2). Overexpression of one of the MYC genes as a result of chromosomal translocation, gene amplification, or loss of negative transcriptional control plays a prominent role in the etiology of many types of tumors (for a review, see Refs. 3 and 4). The MYCN gene is found amplified in several tumors of mostly neuroendocrine origin including about 25% of neuroblastomas, the most common solid tumor in childhood (for a review, see Refs. 5 and 6). Whereas many neuroblastomas regress spontaneously or can be cured with minimal therapy, MYCN-amplified tumors have a poor prognosis. The treatment of these patients has not improved significantly in the course of the last two decades. Recently, the comparison of the gene expression profiles of MYCN-expressing versus non-expressing neuroblastoma cells as well as MYCNamplified versus non-amplified primary tumors have begun to address the functional consequences of the massive overexpression of MYCN resulting from gene amplification (7,8).Several mouse models of Myc-induced tumorigenesis suggest that Myc is not only required for the initiation but also for the maintenance of the tumorigenic state supporting the value of the MYC genes as targets of tumor therapy (9 -11). Roughly half of the drugs that are in clinical use currently act as inhibitors of enzymes. In transcriptional regulation, enzymes are involved mainly as components of signal transduction cascades that relay information to the promoter and as transcriptional co-regulators that modulate local chromatin structure either by covalent modification of histones or by an ATPase-dependent remodeling of nucleosomes (for a review, see Ref. 12). The efficacy of histone deacetylase inhibitors against leukemia has proven the principle of treating cancer by the selective pharmacological modulation of the transcription machinery (13). Application of this concept to the MYCN gene requires a detailed knowledge of the molecular basis of the transcriptional activation of MYCN in neuroblastomas.Toward this goal, we have recently identified the activating members of the E2F family of transcription factors (E2F-1, E2F-2, and E2F-3) as regulators of MYCN expression in neuroblastomas (14). E2F proteins are important regulators of cell-cycle progression, and their activity is negatively controlled by the p16/Rb pathway, which is inactivated in the majority of human cancers (for a review, see Refs. 15 and 16). Although genetic defects of the p16/Rb pathway are rare in neuroblastomas, there is some evidence for a loss of normal control of E2F activity in neuroblastomas by epigenetic means (17).In addition to E2F binding sites, the MYCN promoter contains several putative binding sites for Sp1 and related zinc finger transcription factors (18). One of these, a non-consensus binding site, the CT-box, was previously impli...

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“…Interestingly, the collaborative activity between MYCN and BMI1 may be switched on by a single initiating event, as deregulated E2F1 activity, which is a characteristic lesion in highly proliferative neuroblastoma tumors, 95 is capable of directly driving the expression of both oncogenes. 81,96 The role of BMI1 in neuroblastoma pathogenesis seems not to be limited to MYCN-amplified tumors, as BMI1 is also expressed and required for tumorigenicity in neuroblastoma cells with a normal copy number of MYCN. 82 In line with the requirement Inactivation of p53 in neuroblastoma T Van Maerken et al of BMI1 activity in self-renewal of neural stem cells, it has been argued that BMI1 may be of critical importance for the maintenance of neuroblastoma stem cells by regulating clonogenic self-renewal and multilineage differentiation, offering an attractive target for therapeutic intervention.…”

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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E2F Proteins Regulate MYCN Expression in Neuroblastomas

Cited by 63 publications

References 48 publications

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

E2F and Sp1/Sp3 Synergize but Are Not Sufficient to Activate the MYCN Gene in Neuroblastomas

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

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