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

Authors: Jansson, M. D.; Damas, N. D.; Lees, M.; Jacobsen, A.; Lund, A. H.
Article Title: miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2
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.
Keywords: genetics; cell proliferation; metabolism; microrna; down-regulation; pathology; cell line, tumor; transfection; breast neoplasms; protein p53; physiology; genetic transfection; breast tumor; tumor cell line; tumor suppressor protein p53; down regulation; micrornas; tp53 protein, human; mcf-7 cells; protein mdm2; proto-oncogene proteins c-mdm2; mdm2 protein, human; hek293 cells; humans; human; female; hek293 cell line; mcf 7 cell line; mirn339 microrna, human
Journal Title: Oncogene
Volume: 34
Issue: 15
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2015-04-09
Start Page: 1908
End Page: 1918
Language: English
DOI: 10.1038/onc.2014.130
PUBMED: 24882579
PROVIDER: scopus
Notes: Export Date: 2 July 2015 -- Source: Scopus
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