Extra-Ribosomal Roles for Ribosomal Proteins and Their Relevance to Tumour Suppression, Carcinogenesis and Cancer Progression

Abstract

Protein translation by ribosomes is one of the most energetically costly cellular processes. Consequently, the number and activity of ribosomes in cells and tissues are precisely tailored to match metabolic demands. While ribosomal proteins (RPs) play essential roles in facilitating and regulating the translation of mRNA transcripts into protein, there is increasing evidence that free RPs not bound to ribosomes can play important roles in cellular regulation. Often, free RPs act as tumour suppressors by multiple mechanisms, for example, by inducing cell cycle arrest through their ability to bind and inhibit MDM2-mediated p53 degradation. Dysregulation of these RPs, however, can result in various diseases like Diamond-Blackfan anemia, ribosomopathies, and other diseases. In cancer, epigenetic modifications, altered transcription, and processing defects in the rRNAs create “onco-ribosomes” that strongly support tumour cell replication, invasion and metastasis. In this context, free RPs in tumour cells (often mutated or post-translationally modified) further promote tumour cell proliferation, invasion, and metastasis. This review focuses specifically on extra-ribosomal roles for RPs, where depending upon cellular context, they act outside of the ribosome to either suppress tumorigenesis in normal tissues or promote tumour proliferation and progression. This new understanding of the interplay between RPs and pathways suppressing or promoting tumorigenesis further emphasizes why the ribosome is increasingly being seen as an important therapeutic target in human cancers.