The Role of MDM2 in Promoting Genome Stability versus Instability.

M Saadatzadeh,Pankita Pandya,Adily Elmi,Aaron Cohen-Gadol,Khadijeh Bijangi-Vishehsaraei,Jixin Ding,Karen Pollok,Christopher Stamatkin

doi:10.3390/ijms18102216

Abstract

In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.

Highlights

A number of mouse double minute 2 (MDM2) protein–protein interactions contribute to how eukaryotic cells sense, manage, and resolve DNA damaging events
In MDM2 SNP309 estrogen receptor positive (ER+) breast cancer cell lines treated with estrogen, there was an increase in MDM2-C expression in the nucleus and cytoplasm, but this did not lead to degradation or decreased p53 levels [17]
The integration of signals emanating from the multi-faceted MDM2 signaling network dictates to a large extent, whether cells commit to cell death or survival

Summary

Introduction

A number of mouse double minute 2 (MDM2) protein–protein interactions contribute to how eukaryotic cells sense, manage, and resolve DNA damaging events. In MDM2 SNP309 estrogen receptor positive (ER+) breast cancer cell lines treated with estrogen, there was an increase in MDM2-C expression in the nucleus and cytoplasm, but this did not lead to degradation or decreased p53 levels [17]. Promotion of tumorigenesis can be attributed to the fact that MDM2 and its isoforms play a role in noncanonical p53-independent mechanisms that regulate the cell cycle, DNA repair, and cell differentiation [24,25]. Increased expression of MDM2-C (85 kDa) in human cancer cells and/or tissues of breast cancer, osteosarcoma, and chronic myelogenous leukemia p53 independent transformation function; does not function by inhibiting p53 transcriptional activity and does not show role in p53 degradation pathway p53-independent function for cell proliferation; MDM2-C lacks p53 binding domain but exact mechanism requires further investigation. In cancers where gene amplification is associated with increased MDMX protein expression, this would presumably increase the MDM2 E3 ligase activity leading to downregulation of p53 protein and increased survival of cancer cells [44]

Role of DNA Damage in Stability and Modification of MDM2

Therapeutic Considerations and Conclusi

Findings

Therapeutic Considerations and Conclusions