Signaling to p53: ribosomal proteins find their way

Abstract

Inherently disparate cell growth and division, which are intimately coupled through a delicate network of intracellular and extracellular signaling, require ribosomal biogenesis. A number of events imparting instability to ribosomal biogenesis can cause nucleolar stress. In response to this stress, several ribosomal proteins bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation, resulting in p53-dependent cell cycle arrest. By doing so, the ribosomal proteins play a crucial role in connecting deregulated cell growth with inhibition of cell division. The ribosomal protein-MDM2-p53 signaling pathway provides a molecular switch that may constitute a surveillance network monitoring the integrity of ribosomal biogenesis.

Figure 1. Schematic of RP-MDM2-p53 pathway regulation by nucleolar stress

Under normal growth conditions (no stress), small (S, 40S) and large (L, 60S) RPs are assembled in the nucleolus (NO) and transported to the cytoplasm (CP) for protein synthesis. Under nucleolar stress, ribosomal biogenesis is inhibited and Ribosome-free forms of RPs (RPL and RPS) enter the nucleoplasm (NP) to interact with MDM2, resulting in p53 stabilization and activation. Similarly, RPs either released from breaking down (indicated by wavy edges) of cytoplasmic Ribosomes or overproduced in the cytoplasm can enter the nucleoplasm to interact with MDM2.