title: miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress.
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.
authors: 1] Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [2] Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors: L
authors: L
authors: Lezina
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors: N
authors: N
authors: Purmessur
authors: MRC Toxicology Unit, Leicester LE1 9HN, UK.
authors: A V
authors: AV
authors: Antonov
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors: T
authors: T
authors: Ivanova
authors: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors: E
authors: E
authors: Karpova
authors: Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors: K
authors: K
authors: Krishan
authors: Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors: M
authors: M
authors: Ivan
authors: Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors: V
authors: V
authors: Aksenova
authors: Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors: D
authors: D
authors: Tentler
authors: Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia.
authors: A V
authors: AV
authors: Garabadgiu
authors: 1] Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [2] MRC Toxicology Unit, Leicester LE1 9HN, UK [3] Faculty of Medicine, University of Rome 'Tor Vergata', Rome 00133, Italy.
authors: G
authors: G
authors: Melino
authors: 1] Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [2] Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK [3] Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg 194064, Russia.
authors: N A
authors: NA
authors: Barlev
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D035683:MicroRNAs; D009687:Nuclear Proteins; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C505362:MIRN16 microRNA, human; C528163:MIRN26 microRNA, human; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human