Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer.

Wen Li,Jinyi Lang,Chuan Xu,Xinhao Peng

doi:10.3389/fphar.2020.00631

Abstract

Defects in DNA damage repair may cause genome instability and cancer development. The tumor suppressor gene p53 regulates cell cycle arrest to allow time for DNA repair. The oncoprotein mouse double minute 2 (MDM2) promotes cell survival, proliferation, invasion, and therapeutic resistance in many types of cancer. The major role of MDM2 is to inhibit p53 activity and promote its degradation. In this review, we describe the influence of MDM2 on genomic instability, the role of MDM2 on releasing p53 and binding DNA repair proteins to inhibit repair, and the regulation network of MDM2 including its transcriptional modifications, protein stability, and localization following DNA damage in genome integrity maintenance and in MDM2-p53 axis control. We also discuss p53-dependent and p53 independent oncogenic function of MDM2 and the outcomes of clinical trials that have been used with clinical inhibitors targeting p53-MDM2 to treat certain cancers.

Highlights

Genomic instability is a hallmark of cancer and is regulated by a balance between DNA damage and repair (Aguilera and Garcia-Muse, 2013)
It was found that mouse double minute 2 (MDM2) loss triggered embryonic lethality in mice. Mice deficient in both MDM2 and p53 were rescued from this phenotype leading to normal development and survival. These results suggest the function of MDM2 in negative regulating p53 activity (Jones et al, 1995; Montes et al, 1995)
The results indicated that RG7112 was generally well tolerated with GI toxicities, the most common adverse events (AEs), making it treatable with anti-emetics (Patnaik et al, 2015)

Summary

INTRODUCTION

Genomic instability is a hallmark of cancer and is regulated by a balance between DNA damage and repair (Aguilera and Garcia-Muse, 2013). Studies have identified a single nucleotide polymorphism (T/ G SNP309) in MDM2 promoter region This variant exhibit increased affinity toward the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein (Bond et al, 2004). Following DNA damage, c-Abl binds MDM2 directly, phosphorylates MDM2 at tyrosine 394, and prevents p53 ubiquitination and its nuclear export This c-Abl induced MDM2 tyrosine 394 phosphorylation triggered increased p53 transcription and decreased degradation leading to p53-mediated apoptosis (Sionov et al, 2001; Goldberg et al, 2002). HER-2/neu-mediated Akt activation phosphorylates MDM2 to enhance p300 interaction and inhibits p19ARF interaction, resulting in increased degradation of p53 and blocked cytotoxic effect of DNA damage agents in cancer cells (Zhou et al, 2001). The results indicated that RG7112 was generally well tolerated with GI toxicities, the most common AEs, making it treatable with anti-emetics (Patnaik et al, 2015)

NCT Number

Completed Completed Completed Completed Completed Completed Completed

Completed Completed

CONCLUSION

Findings

AUTHOR CONTRIBUTIONS