Contrasting Behavior of the p18INK4c and p16INK4a Tumor Suppressors in Both Replicative and Oncogene-Induced Senescence

The cyclin-dependent kinase (CDK) inhibitors, p18INK4c and p16INK4a, both have the credentials of tumor suppressors in human cancers and mouse models. For p16INK4a, the underlying rationale is its role in senescence, but the selective force for inactivation of p18INK4c in incipient cancer cells is less clear. Here, we show that in human fibroblasts undergoing replicative or oncogene-induced senescence, there is a marked decline in the levels of p18INK4c protein and RNA, which mirrors the accumulation of p16INK4a. Downregulation of INK4c is not dependent on p16INK4a, and RAS can promote the loss of INK4c without cell-cycle arrest. Downregulation of p18INK4c correlates with reduced expression of menin and E2F1 but is unaffected by acute cell-cycle arrest or inactivation of the retinoblastoma protein (pRb). Collectively, our data question the idea that p18INK4c acts as a backup for loss of p16INK4a and suggest that the apparent activation of p18INK4c in some settings represents delayed senescence rather than increased expression. We propose that the contrasting behavior of the two very similar INK4 proteins could reflect their respective roles in senescence versus differentiation. Cancer Res; 72(1); 165–75. ©2011 AACR.