Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21(Waf1/Cip1)

Oncogene. 2010 Apr 15;29(15):2262-71. doi: 10.1038/onc.2009.497. Epub 2010 Jan 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Cycle / genetics
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p21 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism
  • MicroRNAs / genetics*
  • RNA, Small Interfering / genetics
  • Up-Regulation
  • ras Proteins / metabolism*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MicroRNAs
  • RNA, Small Interfering
  • ras Proteins