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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 is positively regulated by miR-542-3p
Yemin Wang1, Jen-Wei Huang2, Maria Castella3
1Authors' 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.
Abstract:
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.
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