Research Paper Volume 16, Issue 5 pp 4116—4137

Figure 1. Working model for the regulation of the p16/RB pathway and senescence induction by PR55α. Black lines depict our current understanding of the respective roles of the p16/RB and p53/p21 pathways in the promotion of cellular senescence in response to genotoxic stressors [83, 84]. The CDKN2A locus produces both the p16 (INK4a) and p14 (ARF) proteins using both separate promoters and alternative splicing. The p16 protein blocks the CDK4/6 kinases leading to RB activation, which is required for G1 cell cycle arrest and senescence induction. The p14 protein stabilizes p53 by inhibiting the MDM2 E3 ubiquitin ligase, resulting in p21 (a p53 target gene) induction and subsequent inhibition of CDK2 and CDK4/6, which also leads to RB activation that promotes G1 cell cycle arrest and senescence. We have previously reported that p53 negatively regulates PR55α protein stability [28]. However, the p53 mutational status had no detectable impact on the effects of PR55α on the expression of p16 and induction of senescence by IR. Red lines depict novel findings presented in this report: (1) PR55α-controlled PP2A enhances IR-induced p53/p21 signaling and (2) PR55α inhibits p16 transcription independently of p53 function.