Search

The tumor suppressor ARF induces a p53-dependent and -independent cell cycle arrest. Unlike nucleoplasmic localized MDM2 and p53, ARF localizes in the nucleolus. The role of ARF in the nucleolus and the molecular target and mechanism of ARF's p53-independent function remain both controversial and a fertile field of research. Recent study has identified the nucleolar protein B23 as a target of ARF for implementing its growth inhibitory function. The ability of ARF to block cell cycle progression through the MDM2-p53 pathway and to suppress ribosomal biogenesis through B23 suggest a role for ARF in coordinating inhibitions of growth and proliferation.

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.