Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21Waf1/Cip1 (original) (raw)

• Original Article
• Published: 25 January 2010
• M E Lleonart2 na1,
• C L Bishop1,
• D Fessart1,
• A H Bergin1,
• M G Overhoff1 &
• …
• D H Beach1

Oncogene volume 29, pages 2262–2271 (2010)Cite this article

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Abstract

Overexpression of RasG12V in primary cells induces a permanent growth arrest called oncogene-induced senescence (OIS) that serves as a fail-safe mechanism against malignant transformation. We have performed a genome-wide small interfering RNA (siRNA) screen and a microRNA (miRNA) screen to identify mediators of OIS and show that siRNA-mediated knockdown of p21Waf1/Cip1 rescues from RasG12V-induced senescence in human mammary epithelial cells (HMECs). Moreover, we isolated a total of 28 miRNAs that prevented RasG12V-induced growth arrest, among which all of the miR-106b family members were present. In addition, we obtained a number of hits, miR-130b, miR-302a, miR-302b, miR302c, miR-302d, miR-512-3p and miR-515-3p with seed sequences very similar to miR-106b family members. We show that overexpression of all these miRNAs rescues HMECs from RasG12V-induced senescence by prevention of RasG12V-induced upregulation of p21Waf1/Cip1. Our results establish an important role for the cell cycle inhibitor p21Waf1/Cip1 in growth control of HMECs and extend the repertoire of miRNAs that modulate the activity of this tumour suppressor.

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Acknowledgements

This study was funded by Wellcome Programme Grant DERG1C3R (Viola Borgdorff, Marita G Overhoff); Marató TV3 Grant 052130-TV3 (Matilde E Lleonart); AGAUR fellowship 2007 BE-1 00296 (Matilde E Lleonart); MRC Project Grant DERB1A4R (Cleo L Bishop, Ann-Marie H Bergin); CRUK Project Grant DERG1F2R (Delphine Fessart). MELL is a FIS (Fondo de Investigación Sanitario) investigator (CP03/00101).

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Author notes

1. V Borgdorff
   Present address: 4Current address: DIAID, Department of Dermatology, Medical University of Vienna, and Center of Molecular Medicine, Austrian Academy of Sciences, Waehringer Guertel 18-20, Vienna A-1090, Austria.,
2. V Borgdorff and M E Lleonart: These authors contributed equally to this work.

Authors and Affiliations

1. Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK
   V Borgdorff, C L Bishop, D Fessart, A H Bergin, M G Overhoff & D H Beach
2. Pathology Department, Institut de Recerca Hospital Vall d’Hebron, Barcelona, Spain
   M E Lleonart

Authors

1. V Borgdorff
2. M E Lleonart
3. C L Bishop
4. D Fessart
5. A H Bergin
6. M G Overhoff
7. D H Beach

Corresponding author

Correspondence toD H Beach.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Borgdorff, V., Lleonart, M., Bishop, C. et al. Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21Waf1/Cip1.Oncogene 29, 2262–2271 (2010). https://doi.org/10.1038/onc.2009.497

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• Received: 04 June 2009
• Revised: 08 December 2009
• Accepted: 15 December 2009
• Published: 25 January 2010
• Issue date: 15 April 2010
• DOI: https://doi.org/10.1038/onc.2009.497

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