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Negative regulation of the tumor suppressor p53 gene by microRNAs

Oncogene volume 30, pages 843–853 (2011)Cite this article

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Abstract

The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3′UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.

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Acknowledgements

Y L is supported by the Director's Biomarker Award from the Center for Environmental Genomics and Integrative Biology, funded by NIEHS/NIH (P30ES014443), Kentucky Lung Cancer Research Program, NCI/NIH (R01CA138688) and NCRR/NIH (P20 RR024489). K H Y is supported by the University of Wisconsin Paul Carbone Comprehensive Cancer Center Award, the Gundersen Medical Foundation Award, the University of Wisconsin Pathology R & D Fund and by NCI/NIH (P20CA103697 and 1RC1CA146299). We are grateful to the critical reviews from Drs Korise E Rasmusson and Nancy C Martin.Authorship contributions: MK, ZL, AT and WC performed research; NC and KY contributed human specimens; ZL, MK, KR, KY and YL designed research, analyzed data and wrote the paper; and all authors reviewed the paper.

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Author notes

  1. M Kumar

    Present address: 3Current address: Department of Biotechnology, Assam University, Silchar-788011, Assam, India.,

  2. Z Lu & W Chen

    Present address: 4Current address: Department of Medical Laboratory and Central Laboratory, The Central Hospital of Wuhan, Wuhan, Hubei 430014, PR China.,

  3. M Kumar, Z Lu and A A L Takwi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, Louisville, KY, USA

    M Kumar, Z Lu, A A L Takwi, W Chen, K S Ramos & Y Li

  2. Department of Pathology and Laboratory Medicine/Oncology, Paul P Carbone Comprehensive Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    N S Callander & K H Young

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  1. M Kumar
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Correspondence to Y Li.

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Kumar, M., Lu, Z., Takwi, A. et al. Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene 30, 843–853 (2011). https://doi.org/10.1038/onc.2010.457

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