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

Ochiai, Hirotaka; Takenobu, Hisanori; Nakagawa, Atsuko; Yamaguchi, Y; Kimura, Masaki; Ohira, Miki; Okimoto, Yuri; Fujimura, Yu-ichi; Koseki, Haruhiko; Kohno, Yoshiumi; Nakagawara, Akira; Kamijo, Takehiko

doi:10.1038/onc.2010.22

Cited by 80 publications

(68 citation statements)

References 44 publications

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“…Moreover, Bmi1 mRNA expression was induced by MycN in a stepwise manner during tumorigenesis, consistent with a recent study showing that MycN induced Bmi1 transcription. 20 The presence of high Bmi1 levels in both cancer precursor cells and normal perinatal cells is consistent with its role in the regulation of stem cell maintenance and renewal, as well as in the development and progression of human cancers. 19 Normal differentiated cells have an equilibrium between the expression levels of pro-apoptotic and antiapoptotic proteins.…”

Section: Discussionsupporting

confidence: 54%

“…Bmi1 was first described as an oncogene cooperating with c-Myc during the initiation of lymphomas 17,18 and its upregulation has frequently been observed in many human cancers, 19 including neuroblastoma. 13,20 Bmi1 expression has an important role in both the development and maintenance of cancer stem cells by conferring on them stem-like properties, such as resistance to death signaling. 21 Some molecular mechanisms underlying the regulation of apoptosis and differentiation by Bmi1 have been proposed, such as repression of the tumor suppressors p16 INK4a and p19 ARF (p14 ARF in humans), 19 but other mechanisms are likely to be involved.…”

Section: Introductionmentioning

confidence: 99%

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Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation

et al. 2012

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Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN þ / þ transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation

et al. 2012

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“…N-myc can enhance the production of pluripotent and neural tumor stem cells and regulate the expression of ESC factors, including lif, klf2, klf4, and lin28b (57). N-myc also upregulates expression of the self-renewal protein BMI1 in neuroblastoma by directly binding to the E-Box sites within the promoter of BMI1 (58). These findings suggest potential mechanisms by which N-myc may contribute to dedifferentiation and maintenance of a pluripotent state.…”

Section: Functional Targets Of N-mycmentioning

confidence: 88%

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Beltran

2014

Molecular Cancer Research

124

116

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N-myc (MYCN), a member of the Myc family of basic-helix-loop-helix-zipper (bHLHZ) transcription factors, is a central regulator of many vital cellular processes. As such, N-myc is well recognized for its classic oncogenic activity and association with human neuroblastoma. Amplification and overexpression of N-myc has been described in other tumor types, particularly those of neural origin and neuroendocrine tumors. This review outlines N-myc's contribution to normal development and oncogenic progression. In addition, it highlights relevant transcriptional targets and mechanisms of regulation. Finally, the clinical implications of N-Myc as a biomarker and potential as a target using novel therapeutic approaches are discussed. Mol Cancer Res; 12(6); 815-22. Ó2014 AACR. IntroductionThe N-myc gene was first reported in 1983, when Schwab and colleagues (1) and Kohl and colleagues (2) discovered that there were a subset of human neuroblastoma cell lines harboring multiple copies of a DNA sequence related to the C-myc oncogene (MYC), and this region was designated Nmyc (MYCN). Genomic amplification of N-myc resulted in overexpression of N-myc at the mRNA level, and rat embryo cells transfected with N-myc demonstrated oncogenic properties. These findings were first to bring attention to N-myc as a putative oncogene.

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“…We speculate that MYCN is one of the components that enhance the SCD phenotype, and that there may be additional positive regulators; one such candidate is Bmi-1, which is overexpressed in MYCN-amplified cells (35)(36)(37) and required for the self-renewal of stem cells in the peripheral and central nervous system (38). In addition, β-catenin staining in the present study shows that whereas the tight junctions were completely formed in cells with a single copy of MYCN (SH-SY5Y), those were partly [TGW and SK-N-BE (2)] or completely (SK-N-DZ) disrupted in cells with MYCN amplification (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evidence of asymmetric cell division and centrosome inheritance in human neuroblastoma cells

Izumi

Kaneko

2012

Proc. Natl. Acad. Sci. U.S.A.

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Asymmetric cell division (ACD) is believed to be a physiological event that occurs during development and tissue homeostasis in a large variety of organisms. ACD produces two unequal daughter cells, one of which resembles a multipotent stem and/or progenitor cell, whereas the other has potential for differentiation. Although recent studies have shown that the balance between self-renewal and differentiation potentials is precisely controlled and that alterations in the balance may lead to tumorigenesis in Drosophila neuroblasts, it is largely unknown whether human cancer cells directly show ACD in an evolutionarily conserved manner. Here, we show that the conserved polarity/spindle protein NuMA is preferentially localized to one side of the cell cortex during cell division, generating unequal inheritance of fate-altering molecules in human neuroblastoma cell lines. We also show that the cells with a single copy of MYCN showed significantly higher percentages of ACD than those with MYCN amplification. Moreover, suppression of MYCN in MYCN-amplified cells caused ACD, whereas expression of MYCN in MYCN-nonamplified cells enhanced symmetric cell division. Furthermore, we demonstrate that centrosome inheritance follows a definite rule in ACD: The daughter centrosome with younger mother centriole is inherited to the daughter cell with NuMA preferentially localized to the cell cortex, whereas the mother centrosome with the older mother centriole migrates to the other daughter cell. Thus, the mechanisms of cell division of ACD or symmetric cell division and centrosome inheritance are recapitulated in human cancer cells, and these findings may facilitate studies on cancer stem cells.

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

Cited by 80 publications

References 44 publications

Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation

Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Evidence of asymmetric cell division and centrosome inheritance in human neuroblastoma cells

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