Re-thinking the role of ribosomal proteins in the Mdm2-p53 axis

The Mdm2-p53 axis is an important pathway in cells that is frequently misregulated in cancer. Under basal conditions, Mdm2 suppresses p53 through multiple mechanisms. However, when stress is encountered, this suppression is lifted and p53 transactivates the expression of many target genes to effect outcomes such as cell cycle arrest and apoptosis. One type of stress that can activate p53 is ribosomal stress, also called nucleolar stress. Ribosomal stress occurs when mishaps occur in ribosomal biogenesis, and various ribosomal proteins (RPs) have been shown to signal to Mdm2 and activate p53. This thesis presents two studies in the regulation of the Mdm2-p53 axis by ribosomal proteins. In the first study, three ribosomal proteins are newly linked to the Mdm2-p53 axis. RPL37, RPS15, and RPS20 are shown to bind to Mdm2, inhibit its E3 ubiquitin ligase activity towards itself and p53, upregulate various p53, and cause both G2 arrest and apoptosis. Additionally, they downregulate levels of MdmX, a homolog of Mdm2 that also suppresses p53 activity. In the second study, a novel extra-ribosomal function has been identified for RPL36A. Unlike other ribosomal proteins that interact with and activate the Mdm2-p53 axis, RPL36A represses it. RPL36A enhances the E3 ubiquitin ligase activity of Mdm2, downregulates p53 levels, and inhibits the response to ribosomal stress.