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.
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M D
authors.initials: MD
authors.lastname: Jansson
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: N D
authors.initials: ND
authors.lastname: Damas
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Lees
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jacobsen
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A H
authors.identifier: 0000000274073398
authors.initials: AH
authors.lastname: Lund
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C543820:MIRN339 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2