p53 is positively regulated by miR-542-3p.
The tumor suppressor p53 and miRNAs are linked through a complex network. Several miRNAs modulate p53 expression, while p53 regulates the transcription and/or biogenesis of several other miRNAs. Here, we report the development of a cell-based assay used with a library of human miRNA mimics in a high-throughput screen for miRNAs that modulate p53 expression. Overexpression of miRNA (miR)-542-3p in cancer cells elevated p53 expression, stimulated the expression of p53 targets, and inhibited cell proliferation. Mechanistically, miR-542-3p increased p53 protein stability by weakening interactions between p53 and its negative regulator MDM2. Furthermore, miR-542-3p suppressed ribosome biogenesis by downregulating a subset of ribosomal proteins such as RPS23, leading to upregulation of RPL11 and stabilization of p53. The 3'untranslated region in the RPS23 transcript contained a miR-542-3p-binding site, suggesting that RPS23 is a direct target of miR-542-3p. Our results define miR-542-3p as an important new positive regulator of p53 with potential applications in cancer treatment.
Authors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, CanadaAuthors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada ttaniguc@fhcrc.org yewang@bccrc.ca.
Yemin
Y
Wang
Authors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, CanadaAuthors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada.
Jen-Wei
JW
Huang
Authors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada.
Maria
M
Castella
Authors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada.
David George
DG
Huntsman
Authors' Affiliations: Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center; Molecular & Cellular Biology Program, University of Washington, Seattle, Washington; and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada ttaniguc@fhcrc.org yewang@bccrc.ca.
Toshiyasu
T
Taniguchi
D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D020413:3' Untranslated Regions; C572357:MIRN542 microRNA, human; D035683:MicroRNAs; C484213:RPS23 protein, human; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2