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miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression

Oncogene volume 28, pages 140–145 (2009)Cite this article

Abstract

The stringent regulation of cell cycle progression helps to maintain genetic stability in cells. MicroRNAs (miRNAs) are critical regulators of gene expression in diverse cellular pathways, including developmental patterning, hematopoietic differentiation and antiviral defense. Here, we show that two c-Myc-regulated miRNAs, miR-17 and miR-20a, govern the transition through G1 in normal diploid human cells. Inhibition of these miRNAs leads to a G1 checkpoint due to an accumulation of DNA double-strand breaks, resulting from premature temporal accumulation of the E2F1 transcription factor. Surprisingly, gross changes in E2F1 levels were not required to initiate the DNA damage response and checkpoint, as these responses could occur with a less than twofold change in E2F1 protein levels. Instead, our findings indicate that the precise timing of E2F1 expression dictates S-phase entry and that accurate timing of E2F1 accumulation requires converging signals from the Rb/E2F pathway and the c-Myc-regulated miR-17 and miR-20a miRNAs to circumvent a G1 checkpoint arising from the untimely accumulation of E2F1. These data provide a mechanistic view of miRNA-based regulation of E2F1 in the context of the emerging model that miRNAs coordinate the timing of cell cycle progression.

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Acknowledgements

This study was supported in parts by research grants from the March of Dimes Foundation (6-FY06-344) and the NIH (AI0766189 and 5 P30 DK32520). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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  1. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA

    M T Pickering, B M Stadler & T F Kowalik

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  1. M T Pickering
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  2. B M Stadler
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  3. T F Kowalik
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Correspondence to T F Kowalik.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Pickering, M., Stadler, B. & Kowalik, T. miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene 28, 140–145 (2009). https://doi.org/10.1038/onc.2008.372

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