The RP-Mdm2-p53 pathway and tumorigenesis

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.

Figure 1. Mdm2 conveys stress signals to p53 through multiple pathways

Changes in nutrient availability or treatment with low doses of Actinomycin D lead to nucleolar (ribosomal) stress. As a result, ribosomal proteins L5 and L11 bind to and inhibit the E3 ligase function of Mdm2, resulting in p53 stabilization and activation. In addition, oncogenic insults, such as aberrant expression of c-Myc, induce the expression of both p19^ARF and ribosomal proteins. The RP-MDM2-p53 and p19^ARF-Mdm2-p53 represent two parallel signaling pathways in response to oncogenic c-Myc stimulation.