Journal
ONCOGENE
Volume 29, Issue 15, Pages 2262-2271Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.497
Keywords
oncogene-induced senescence; Ras; siRNA; miRNA; p21(Waf1/Cip1)
Funding
- Wellcome Programme [DERG1C3R]
- Marato TV3 Grant [052130-TV3]
- AGAUR [2007 BE-1 00296]
- MRC [DERB1A4R]
- CRUK [DERG1F2R]
- MRC [G0500357] Funding Source: UKRI
- Medical Research Council [G0500357] Funding Source: researchfish
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Overexpression of Ras(G12V) 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 p21(Waf1/Cip1) rescues from Ras(G12V)-induced senescence in human mammary epithelial cells (HMECs). Moreover, we isolated a total of 28 miRNAs that prevented Ras(G12V)-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 Ras(G12V)-induced senescence by prevention of Ras(G12V)-induced upregulation of p21(Waf1/Cip1). Our results establish an important role for the cell cycle inhibitor p21(Waf1/Cip1) in growth control of HMECs and extend the repertoire of miRNAs that modulate the activity of this tumour suppressor. Oncogene (2010) 29, 2262-2271; doi: 10.1038/onc.2009.497; published online 25 January 2010
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