Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21Waf1/Cip1.

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. [ABSTRACT FROM AUTHOR]