Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation, their ribosome-independent functions have also been greatly appreciated. Over the past decade, more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress. In addition, these ribosomal proteins are involved in various physiological and pathological processes. This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins, as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis, immune signaling, and development. We also propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.

Genomic sequencing analyses of a variety of human cancers have revealed that massive mutations of cancer-relevant genes are the major alterations in cancerous cells, and their mutation frequencies or rates are highly associated with the development, progression, metastasis, and drug resistance of cancers as well as their clinical outcomes and prognosis. One predominant genetic alternation in human epithelial ovarian cancer (EOC) is the mutation of TP53 that encodes the tumor suppressor p53 protein. This essay will review the most recent progress in understanding the role of TP53 mutations in development, progression, and metastasis of EOC, and discuss the potential of TP53 mutations as diagnostic and prognostic biomarkers as well as therapeutic targets for EOC.

Although ∼50% of all types of human cancers harbour wild‐type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53‐dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2‐mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour‐specific apoptosis, and represses the growth of xenograft tumours derived from p53‐harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour‐bearing SCID mice. Hence, our study unearths INZ as a novel anti‐cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.

AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX–14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations. Moreover, deficiency of AMPK prevented MDMX–14-3-3 interaction and p53 activation. The activation of p53 through AMPK-mediated MDMX phosphorylation and inactivation was further confirmed by using cell and animal model systems with two AMPK activators, metformin and salicylate (the active form of aspirin). Together, the results unveil a mechanism by which metabolic stresses activate AMPK, which, in turn, phosphorylates and inactivates MDMX, resulting in p53 stabilization and activation.

The oncoprotein MDM2 is both the transcriptional target and the predominant antagonist of the tumor suppressor p53. MDM2 inhibits the functions of p53 via a negative feedback loop that can be circumvented by several ribosomal proteins in response to nucleolar or ribosomal stress. Stress conditions in the nucleolus can be triggered by a variety of extracellular and intracellular insults that impair ribosomal biogenesis and function, such as chemicals, nutrient deprivation, DNA damaging agents, or genetic alterations. The past decade has witnessed a tremendous progress in understanding this previously underinvestigated ribosomal stress-MDM2-p53 pathway. Here, we review the recent progress in understanding this unique signaling pathway, discuss its biological and pathological significance, and share with readers our insight into the research in this field.