Bmi-1 Regulates the Differentiation and Clonogenic Self-renewal of I-type Neuroblastoma Cells in a Concentration-dependent Manner

Cui, Hongjuan; Ma, Jun; Ding, Jane; Li, Tai; Alam, Goleeta N.; Ding, Han‐Fei

doi:10.1074/jbc.m604009200

Cited by 75 publications

(81 citation statements)

References 36 publications

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“…In addition, we found an additive effect of MYCN induction in Bmi1-expressing Tet21/N cells, suggesting the significance of MYCN targets, except for Bmi1, in NB cell proliferation. Bmi1 knockdown by lentivirusmediated shRNA transduction strongly inhibited cell Figure S3 and data not shown), consistent with previous reports (Cui et al, 2006).…”

Section: Mycn-induced Bmi1 Represses Tumor Suppressorssupporting

confidence: 92%

“…However, Bmi1 expression was not evaluated according to patient prognosis, and there was no correlation between MYCN amplification and Bmi1 expression in the report. Another group reported that Bmi1 suppression by knockdown induced several differentiation marker proteins, and impaired colony formation and tumor formation in immunodeficient mice, although Bmi1 overexpression in NB cells could not function as an oncogene (Cui et al, 2006(Cui et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

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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: Mycn-induced Bmi1 Represses Tumor Suppressorssupporting

confidence: 92%

Section: Introductionmentioning

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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“…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. 97 Repression of p14 ARF -p53 Signaling by Loss of CHD5…”

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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“…For knockdown of Bmi-1 and Ring2, vectors expressing the following hairpin RNAs were transfected into 293T cells with other package plasmids, supernatant were collected after 48 h and added to HeLa cells that were of 40% confluence. Samples were collected after 48 h. The three RNAi target Bmi-1 are as follows: BRNAi1, 5Ј-ATATTGTATACAAATTAG; BRNAi2, 5Ј-AAGGAATGGTC-CACTTCCATT; BRNAi3, 5Ј-ATGAAGAGAAGAAGGGATT (27,28). Three Bmi-1-si constructions all worked well and only Bmi-1-Si-2 related results were shown in this study.…”

Section: Modification Of Vector and P16mentioning

confidence: 99%

Identification and Characterization of Bmi-1-responding Element within the Human p16 Promoter*

Meng

Luo

Sun

et al. 2010

Journal of Biological Chemistry

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Bmi-1, the first functionally identified polycomb gene family member, plays critical roles in cell cycle regulation, cell immortalization, and cell senescence. Bmi-1 is involved in the development and progression of carcinomas and is a potent target for cancer therapy. One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16 Ink4a and p19Arf , as Bmi-1 represses the INK4a locus on which they are encoded. A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear. In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter. The BRE resided at bp ؊821 to ؊732 upstream of the p16 ATG codon. BRE alone was sufficient to allow Bmi-1-mediated regulation of the CMV promoter. Bmi-1 typically functions by forming a complex with Ring2; however, regulation of p16 was independent of Ring2. Chromatin immunoprecipitation sequencing of Bmi-1-precipitated chromatin DNA revealed that 1536 genes were targeted by Bmi-1, including genes involved in tissue-specific differentiation, cell cycle, and apoptosis. By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation. Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy.

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Bmi-1 Regulates the Differentiation and Clonogenic Self-renewal of I-type Neuroblastoma Cells in a Concentration-dependent Manner

Cited by 75 publications

References 36 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

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

Identification and Characterization of Bmi-1-responding Element within the Human p16 Promoter*

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