Abstract
Several ribosomal proteins (RPs) in response to various ribosomal stressors have been shown to play a critical role in p53-dependent regulation of cell cycle arrest, apoptosis and tumor suppression. Here, we report ribosomal protein L22 (RPL22/eL22) as a novel p53 activator highly mutated (mostly deletion mutation) in various types of human cancers, but not essential for ribosomal biogenesis in normal cells. Ectopic expression of RPL22/eL22 suppressed the colony formation of cancer cells in a p53-dependent manner, whereas knockdown of RPL22/eL22 significantly compromised p53 activation by Actinomycin D, rescuing p53-induced G1/G0 cell cycle arrest. Interestingly, human tumors with RPL22/eL22 deletion appeared to sustain wild type p53. Mechanistically, RPL22/eL22 bound to MDM2 acidic domain and inhibited MDM2-mediated p53 ubiquitination and degradation, hence extending the half-life of p53. Ribosome-profiling analysis revealed that induction of ribosomal stress by Actinomycin D leads to the increase of ribosome-free RPL22/eL22 pool. Also, RPL22/eL22 formed a complex with MDM2/RPL5/uL18/RPL11/uL5 and synergized with RPL11/uL5 to activate p53. Furthermore, the N terminus of RPL22/eL22 bound to MDM2, while the C terminus interacted with RPL5/uL18/RPL11/uL5; both of these two fragments activated p53 by inhibiting MDM2. Our study indicates that RPL22/eL22 highly mutated in human cancers plays an anti-cancer role likely through regulation of the MDM2-p53 feedback loop, and also suggests that targeting the RPL22/eL22-MDM2-p53 pathway could be a potential strategy for future development of anti-cancer therapy.
Highlights
Tumor cells utilize gene mutations to alter cell signal transduction events in favor of cell survival
RPL22/eL22 can bind to Epstein-Barr virus (EBV) small RNA EBER1, and this binding is responsible for EBER1 growth-promoting capability in Akata Burkitt lymphoma cells [35, 36]
In lymphoid precursors, RPL22/eL22 expression is transcriptionally activated by Miz-1 in response to V(D)J recombination, and elevated RPL22/eL22 subsequently binds to p53 mRNA to www.impactjournals.com/oncotarget suppress its translation, preventing p53 from inducing cell death [7]
Summary
Tumor cells utilize gene mutations to alter cell signal transduction events in favor of cell survival. A latest report showed that RPL22/eL22 is the most recurrently mutated/deleted ribosomal protein gene (RPG) in 30 cell lines with intact and functional p53, differing from other RPGs that are more likely deleted in TP53-mutated tumors in a large-scale analysis of human cancer genome data [5]. These studies suggest that RPL22/ eL22 is a potential tumor suppressor. It has been shown that RPL22/eL22 deficiency leads to the activation of the tumor suppressor p53 in immune cells, and RPL22/ eL22 may mediate Trp translation via Miz in cells undergoing V(D)J recombination [6, 7], it still remains unknown if RPL22/eL22 might play a possible tumor suppression role by regulating the p53-MDM2 loop in response to ribosomal stress in non immune cells since RPL22/eL22 is ubiquitously expressed in all cells and tissues
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