MiR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress

L. Lezina, N. Purmessur, A. V. Antonov, T. Ivanova, E. Karpova, K. Krishan, M. Ivan, V. Aksenova, D. Tentler, A. V. Garabadgiu, G. Melino, N. A. Barlev

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57 Scopus citations

Abstract

The tumour suppressor p53 is a crucial regulator of cell cycle arrest and apoptosis by acting as a transcription factor to regulate a variety of genes. At least in part, this control is exerted by p53 via regulating expression of numerous microRNAs. We identified two abundantly expressed microRNAs, miR-16 and miR-26a, whose expression is regulated by p53 during the checkpoint arrest induced by the genotoxic drug, doxorubicin. Importantly, among the targets of these miRs are two critical checkpoint kinases, Chk1 and Wee1. The p53-dependent augmentation of miR-16 and miR-26a expression levels led to the cell cycle arrest of tumour cells in G1/S and increased apoptosis. Strikingly, the bioinformatics analysis of survival times for patients with breast and prostate cancers has revealed that co-expression of mir-16 and miR-26a correlated with a better survival outcome. Collectively, our data provide a novel mechanism whereby p53 represses Chk1 and Wee1 expression, at least partially, via upregulation of miR-16 and miR-26a and thus sensitizes tumour cells to genotoxic therapies.

Original languageEnglish (US)
Article numbere953
JournalCell Death and Disease
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2013

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Keywords

  • checkpoint kinases
  • Chk1
  • genotoxic stress
  • microRNAs
  • p53
  • Wee1

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Lezina, L., Purmessur, N., Antonov, A. V., Ivanova, T., Karpova, E., Krishan, K., Ivan, M., Aksenova, V., Tentler, D., Garabadgiu, A. V., Melino, G., & Barlev, N. A. (2013). MiR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress. Cell Death and Disease, 4(12), [e953]. https://doi.org/10.1038/cddis.2013.483