The RP-Mdm2-p53 Pathway and Tumorigenesis

Paula L Miliani De Marval,Yanping Zhang

doi:10.18632/oncotarget.228

Abstract

The dynamic processes of cell growth and division are under constant surveillance. As one of the primary "gatekeepers" of the cell, the p53 tumor suppressor plays a major role in sensing and responding to a variety of stressors to maintain cellular homeostasis. Recent studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. Mutations in Mdm2 that disrupt RP binding have been detected in human cancers; however, the physiological significance of the RP-Mdm2 interaction is not completely understood. We generated mice carrying a single cysteine-to-phenylalanine substitution in the central zinc finger of Mdm2 (Mdm2C305F) that disrupts Mdm2's binding to RPL11 and RPL5. Despite being developmentally normal and maintaining an intact p53 response to DNA damage, the Mdm2C305F mice demonstrate a diminished p53 response to perturbations in ribosomal biogenesis, providing the first in vivo evidence for an RP-Mdm2-p53 signaling pathway. Here we review some recent studies about RP-Mdm2-p53 signaling and speculate on the relevance of this pathway to human cancer.

Highlights

The regulation of ribosome biogenesis is fundamental for cell growth control
The model perceived from a myriad of in vitro data suggested that when cells sense nutrient-shortage stress, ribosomal proteins are released from the nucleolus to the nucleoplasm where they can bind to Mdm2 and inhibit its E3 ligase activity, leading to activation of p53
These data uncovered a novel mechanism for Mdm2 oncogenic activation and a new level of Mdm2-p53 regulation, and together with previous studies, suggest that three distinct modes of p53 regulation exist: phosphorylation of Mdm2 and p53 by various kinases induced by DNA damage, induction of p14ARF-/p19ARF-Mdm2 interaction triggered by oncogenic insults, and the induction of RPMdm2 interaction triggered by signaling malfunctions in ribosomal biogenesis

Summary

Introduction

The regulation of ribosome biogenesis is fundamental for cell growth control. It involves the coordination of multiple steps including synthesis and processing of ribosomal RNA (rRNA), synthesis of ribosomal proteins and their import into the nucleus, assembly of ribosome subunits, transport of the mature 40S and 60S subunits to the cytoplasm, and assembly of 80S ribosome in the cytoplasm. Impaired expression of ribosomal proteins has been associated with various functional consequences including tumorigenesis as well as growth abnormalities in humans and mice [13,14,15].

Results

Conclusion