Ribosomal Proteins Control Tumor Suppressor Pathways in Response to Nucleolar Stress

Ribosome‐free ribosomal proteins accumulate upon nucleolar stress. While some ribosomal proteins inhibit Myc, E2Fs and Mdm2 and activate p53, RPS14 binds and inhibit CDK4‐cyclin D complexes activating the retinoblastoma (RB) pathway. Drugs able to engage the tumor suppressor functions of ribosomal proteins may represent a novel generation of anticancer medicines.

Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre‐ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome‐free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. Recent results on senescence‐associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs.

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