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Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression

Oncogene volume 31, pages 3785–3795 (2012)Cite this article

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Abstract

The Polycomb transcription repressor BMI1 is highly expressed in human neuroblastomas and is required for the clonogenic self-renewal and tumorigenicity of human neuroblastoma cell lines. The molecular basis of BMI1 action in neuroblastoma cells is not well understood. Here we report that BMI1 has a critical role in stabilizing cyclin E1 by repressing the expression of FBXW7, a substrate-recognition subunit of the SCF E3 ubiquitin ligase that targets cyclin E1 for degradation. BMI1 binds to the FBXW7 locus in vivo and represses its mRNA expression. Overexpression of cyclin E1 or abrogation of FBXW7 induction rescues the cell-death phenotype of BMI1 knockdown. Moreover, MYCN, an oncoprotein in the pathogenesis of high-risk neuroblastomas, is able to counteract the death-inducing effect of BMI1 knockdown by activating CCNE1 transcription. We further show that high cyclin E1 expression is associated with Stage 4 neuroblastomas and poor prognosis in patients. These findings suggest a molecular mechanism for the oncogenic activity of BMI1 and MYCN in neuroblastoma pathogenesis and progression by maintaining cyclin E1 levels.

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Acknowledgements

We thank Q Du for pKMyc-cyclinE1, G Hannon and J Silva for shRNAmir Tet-Off, R Mulligan for pHDM-G and pMD.MLVogp, W Wei for pBabe-puro-p14ARF and J Khan for gene expression data sets from the Oncogenomics Database. This work was supported by the NIH grant CA124982 and a Georgia Cancer Coalition Distinguished Scholar Award (H-FD), and a grant from the National Basic Research Program of China (No. 2012cb114603) to HC. LM was supported in part by a grant from the National Science Foundation of China (NSFC 81101905).

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  1. L Mao and J Ding: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Center and Department of Pathology, Cancer Center, Georgia Health Sciences University, Augusta, GA, USA

    L Mao, J Ding, A Perdue, L Yang, Y Zha, M Ren & H-F Ding

  2. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    L Mao

  3. Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China

    Y Zha

  4. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA, USA

    S Huang

  5. The State Key Laboratory of Silkworm Functional Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing, China

    H Cui

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Mao, L., Ding, J., Perdue, A. et al. Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression. Oncogene 31, 3785–3795 (2012). https://doi.org/10.1038/onc.2011.536

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