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MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells

Oncogene volume 31, pages 1342–1353 (2012)Cite this article

Abstract

The MYCN gene has a critical role in determining the clinical behavior of neuroblastoma. Although it is known that genomic amplification occurs in high-risk subsets, it remains unclear how MYCN expression is regulated in the pathogenesis of neuroblastomas. Here, we report that MYCN expression was regulated by the oncoprotein MDM2 at the post-transcriptional level and was associated with neuroblastoma cell growth. Increasing MDM2 by ectopic overexpression in the cytoplasm enhanced both mRNA and protein expression of MYCN. Mechanistic studies found that the C-terminal RING domain of the MDM2 protein bound to the MYCN mRNA's AREs within the 3′UTR and increased MYCN 3′UTR-mediated mRNA stability and translation. Conversely, MDM2 silencing by specific siRNA rendered the MYCN mRNA unstable and reduced the abundance of the MYCN protein in MYCN-amplified neuroblastoma cell lines. Importantly, this MDM2 silencing resulted in a remarkable inhibition of neuroblastoma cell growth and induction of cell death through a p53-independent pathway. Our results indicate that MDM2 has a p53-independent role in the regulation of both MYCN mRNA stabilization and its translation, suggesting that MDM2-mediated MYCN expression is one mechanism associated with growth of MYCN-associated neuroblastoma and disease progression.

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Acknowledgements

This work was supported by the National Institutes of Health (R01 CA123490 and R01CA143107 to MZ) and CURE (MZ and LG).

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  1. L Gu and H Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University School of Medicine, Atlanta, GA, USA

    L Gu, H Zhang, J He, J Li, M Huang & M Zhou

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  1. L Gu
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Correspondence to M Zhou.

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Gu, L., Zhang, H., He, J. et al. MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells. Oncogene 31, 1342–1353 (2012). https://doi.org/10.1038/onc.2011.343

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