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miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2

Oncogene volume 34, pages 1908–1918 (2015)Cite this article

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Abstract

MicroRNAs (miRNAs) regulate many key cancer-relevant pathways and may themselves possess oncogenic or tumor-suppressor functions. Consequently, miRNA dysregulation has been shown to be a prominent feature in many human cancers. The p53 tumor suppressor acts as a negative regulator of cell proliferation in response to stress and represents the most commonly lost and mutated gene in human cancers. The function of p53 is inhibited by the MDM2 oncoprotein. Using a high-throughput screening approach, we identified miR-339-5p as a regulator of the p53 pathway. We demonstrate that this regulation occurs via the ability of miR-339-5p to target directly the 3′-untranslated region of MDM2 mRNA, reducing MDM2 expression and thus promoting p53 function. Consequently, overexpression of miR-339-5p positively impacts on p53-governed cellular responses such as proliferation arrest and senescence, whereas inhibition of miR-339-5p function perturbs the p53 response in cancer cells, allowing an increased proliferation rate. In addition, miR-339-5p expression is downregulated in tumors harboring wild-type TP53, suggesting that reduction of miR-339-5p level helps to suppress the p53 response in p53-competent tumor cells. Furthermore, we show that a negative correlation between miR-339-5p and MDM2 expression exists in human cancer, implying that the interaction is important for cancer development.

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Acknowledgements

Work in the authors’ laboratory was supported by the Danish National Advanced Technology Foundation, the Danish National Research Foundation, the Novo Nordisk Foundation, the Lundbeck Foundation and the Danish Cancer Society. Dr Jansson was supported by a grant from the Danish Medical Research Council. We acknowledge the The Cancer Genome Atlas Research Network for our use of their publically available tumor data sets. We thank Bert Vogelstein and Kristian Helin for cell lines.

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Authors and Affiliations

  1. Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark

    M D Jansson, N D Damas, M Lees & A H Lund

  2. Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Jacobsen

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  1. M D Jansson
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Correspondence to A H Lund.

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Jansson, M., Damas, N., Lees, M. et al. miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2. Oncogene 34, 1908–1918 (2015). https://doi.org/10.1038/onc.2014.130

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