Fig. 2
From: Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy
p53-mediated nucleolar stress response. Cell growth and proliferation remain under constant nucleolar surveillance. Under normal growth conditions, levels of the tumor suppressor p53 are suppressed by the binding of the E3 ubiquitin ligase mouse double minute 2 (Mdm2) and its homolog Mdm4, leading to ubiquitination and degradation of p53. When ribosome biogenesis is disrupted at the level of rRNA synthesis, processing or ribosome assembly, free ribosomal proteins (RPs) (primarily RPL5 and RPL11 and RPL23) and the 5S rRNA are released from the nucleolus to the nucleoplasm where they bind and sequester Mdm2/Mdm4. This in turn prevents the poly-ubiquitination and proteasome-mediated degradation of p53, thereby mediating its stabilization. The RPs (indicated) have been shown to regulate the Mdm2/p53 axis through various mechanisms including binding Mdm2 and its homolog and binding partner Mdm4. Additional mechanisms of nucleolar stress response include ribosome stress-mediated increase in RPL11 mRNA translation, which leads to enhanced interaction between RPL11 and Mdm2 and subsequent accumulation of p53. Following nucleolar stress, p53 can also be activated by RPL26 binding to p53 mRNA and enhancing its translation. Upon activation, p53 transactivates several downstream targets, leading to cell cycle arrest, apoptosis, autophagy or senescence
