Contrasting behavior of the p18 and p16 tumor suppressors in both replicative and oncogene-induced senescence

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The CDK inhibitors, p18 INK4c and p16 INK4a , both have the credentials of tumor suppressors in human cancers and mouse models. For p16 INK4a , the underlying rationale is its role in senescence but the selective force for inactivation of p18 INK4c 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 p18 INK4c protein and RNA, which mirrors the accumulation of p16 INK4a. Down-regulation of INK4c is not dependent on p16 INK4a and RAS can promote the loss of INK4c without cell cycle arrest. Down-regulation of p18 INK4c 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 p18 INK4c acts as a backup for loss of p16 INK4a and suggest that the apparent activation of p18 INK4c 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.