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miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress
L Lezina1, N Purmessur2, A V Antonov3
11] Molecular Pharmacology laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg 190013, Russia [2] Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
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.
Insights
The tumor suppressor p53 regulates miR-16 and miR-26a, which target Chk1 and Wee1 kinases. This p53-mediated pathway enhances cancer cell apoptosis and improves patient survival in breast and prostate cancers.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The tumor suppressor p53 is a key regulator of cell cycle arrest and apoptosis.
- p53 exerts its control partly by regulating microRNA expression.
- MicroRNAs play critical roles in cellular processes and disease.
Purpose of the Study:
- To investigate the role of p53 in regulating microRNA expression during genotoxic stress.
- To identify specific microRNAs regulated by p53 and their targets.
- To elucidate the functional consequences of p53-mediated microRNA regulation in cancer.
Main Methods:
- Doxorubicin treatment to induce genotoxic stress and checkpoint arrest.
- Quantitative real-time PCR to measure microRNA expression levels.
- Bioinformatic analysis to identify microRNA targets and analyze patient survival data.
Main Results:
- p53 upregulates the expression of miR-16 and miR-26a during doxorubicin-induced checkpoint arrest.
- miR-16 and miR-26a target the critical checkpoint kinases Chk1 and Wee1.
- Increased miR-16 and miR-26a levels induce G1/S cell cycle arrest and apoptosis in tumor cells.
- Co-expression of miR-16 and miR-26a correlates with better survival outcomes in breast and prostate cancer patients.
Conclusions:
- p53 sensitizes tumor cells to genotoxic therapy by upregulating miR-16 and miR-26a.
- This mechanism involves the repression of Chk1 and Wee1 expression.
- The findings reveal a novel p53-microRNA pathway impacting cancer progression and treatment response.
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