The RP-p53-Mdm2 pathway

Deregulation of the cell cycle (cell division) has long been known to contribute to the induction of cancer. Similarly, disruption of protein synthesis (cell growth) has also been shown to lead to several pathological conditions including cancer.1 The tumor suppressor p53 is pivotal in inducing cell cycle arrest in response to DNA damage, and it has recently been recognized that p53 also plays a role in linking cell division with cell growth by sensing nucleolar stress.2 When there is stress to ribosome biogenesis, and thus protein synthesis, several ribosomal proteins (RPs) such as RPL11, RPL23 and RPL5 have been shown to interact with Mdm2 and inhibit its E3 ubiquitin ligase activity towards p53. This leads to p53 stabilization and activation and enables cells to stop cell cycle progression in the absence of functional ribosomal biogenesis conditions.3 This places p53 as an important regulator of both the DNA damage and protein synthesis pathways and suggests the coupling of these two processes may be important to preventing oncogenesis.