MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells
Open Access
- 8 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 31 (11), 1342-1353
- https://doi.org/10.1038/onc.2011.343
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.Keywords
This publication has 39 references indexed in Scilit:
- p53 Is a Direct Transcriptional Target of MYCN in NeuroblastomaCancer Research, 2010
- Regulation of XIAP Translation and Induction by MDM2 following IrradiationCancer Cell, 2009
- p73α isoforms drive opposite transcriptional and post-transcriptional regulation of MYCN expression in neuroblastoma cellsNucleic Acids Research, 2008
- Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESsMolecular and Cellular Biology, 2008
- TheMYCNEnigma: Significance ofMYCNExpression in NeuroblastomaCancer Research, 2006
- Metal and RNA Binding Properties of the hdm2 RING Finger DomainBiochemistry, 1998
- Mdm2 promotes the rapid degradation of p53Nature, 1997
- The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivationCell, 1992
- Association of Multiple Copies of the N-mycOncogene with Rapid Progression of NeuroblastomasThe New England Journal of Medicine, 1985
- Amplification of N- myc in Untreated Human Neuroblastomas Correlates with Advanced Disease StageScience, 1984