nhibiting Oncogene-Induced Senescence

Download ammalian cells, activation of oncogenes usually triggers innate tumor-suppressing defense mechanisms, ing apoptosis and senescence, which are compromised by additional mutations before cancers are develThe miR-17-92 gene cluster, a polycistron encoding six microRNAs (miRNA), is frequently overexpressed an cancers and has been shown to promote several aspects of oncogenic transformation, including evaf apoptosis. In the current study, we show a new role of miR-17-92 in inhibiting oncogenic ras-induced ence. Further dissection of the miRNA components in this cluster reveals that the miR-17/20a seed family nts for this antisenescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring nce to ras-induced senescence by directly targeting p21, a key effector of senescence. By contrast, components are not essential for the ability of miR-17-92 to evade Myc-induced apoptosis. Moreover, tion of senescence by miR-17-92 or its miR-17/20a components leads to enhanced oncogenic transforn by activated ras in primary human cells. Taken together with previous reports that miR-17-92 inhibits sis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster proapopto motes tumorigenesis by antagonizing both tumor-suppressing mechanisms, apoptosis, and senescence, through the activities of different miRNA components encoded in this cluster. Cancer Res; 70(21); 8547–57. ©2010 AACR.