It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.

Che-Pei Kung,Jason D Weber

doi:10.3389/fcell.2022.818744

Che-Pei Kung, Jason D Weber

Open Access

https://doi.org/10.3389/fcell.2022.818744

Copy DOI

Abstract

Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the direction of p53 research, as well as the development of p53-based therapeutic strategies for the last 30 years. Our increasing knowledge of this triangle during this time, especially through identification of p53-independent functions of MDM2 and ARF, have uncovered many under-appreciated molecular mechanisms connecting these three proteins. Through recognizing both antagonizing and synergizing relationships among them, our consideration for harnessing these relationships to develop effective cancer therapies needs an update accordingly. In this review, we will re-visit the conventional wisdom regarding p53-MDM2-ARF tumor-regulating mechanisms, highlight impactful studies contributing to the modern look of their relationships, and summarize ongoing efforts to target this pathway for effective cancer treatments. A refreshed appreciation of p53-MDM2-ARF network can bring innovative approaches to develop new generations of genetically-informed and clinically-effective cancer therapies.

Highlights

Discovered more than 40 years ago, tumor-suppressor p53 has become the most popular gene due to the fact that it is the most frequently altered gene in cancers (Vogelstein et al, 2010; Dolgin, 2017)
Does co-inactivation of p53 and alternate open reading frame (ARF) warrant more attention as a defective tumorsuppressive entity, for which independent investigations should be conducted instead of inferring biological meanings from their loss-of-function individually? In addition to common cancer types in which p53/mouse double minute 2 (MDM2)/ARF alterations are prevalent, could we unveil more clinical benefits in rare and pediatric malignancies targeting this axis? Pediatric cancers have much lower mutation burdens compared to adult tumors, but most of their mutations occur in a few significant cancer driver genes, such as TP53 and CDKN2A (Ma et al, 2018) (Figure 5)
Does collective status of all three genes provide additional biomarker values in helping us tailor therapeutic strategies? For example, in cancers with functional p53 and ARF in addition to MDM2 amplification, would p53-MDM2 inhibitors sensitize tumors to ferroptosis-inducing treatments? In ARFdeficient cancers with mutant p53 and MDM2 amplification, could p53/ARF-based therapeutic peptides synergize with MDM2-targeting proteolysis targeting chimera (PROTAC)? With their expanding roles identified in metabolism and tumor microenvironment (TME), could p53/MDM2/ARF-based interventions synergize with metabolic and immunogenic regulations? For example, mitochondrial apoptotic priming through targeting Bcl-2/Bcl-xl was recently found to significantly enhance wild type (WT) p53 activity, and might have similar effects on MDM2/ ARF-targeting treatments (Sánchez-Rivera et al, 2021)

Summary

Introduction

Discovered more than 40 years ago, tumor-suppressor p53 (encoded by TP53 in human and Trp53 in mouse) has become the most popular gene due to the fact that it is the most frequently altered gene in cancers (Vogelstein et al, 2010; Dolgin, 2017). A recent study demonstrated, using an acetylation-defective p53-4KR mouse model, that p53’s ability to suppress mTOR function is linked to distinctive tumor-suppressive activities independent of cell cycle arrest, senescence, and apoptosis (Kon et al, 2021). MDM2-ARF complex, independent of their ability to relocate to nucleolus, promotes SUMO-2/3mediated SUMOylation of p53 to modulate its transcriptional activity (Stindt et al, 2011).

Results

Conclusion