The Role of the Mdm2/MdmX E3 Ligase System in Carcinogenesis, and Current Chemotherapeutic Interventions: A Literature Review

Abstract

Introduction: E3 (ubiquitin) ligases play a major role in the ubiquitin-proteasome system (UPS), responsible for the ubiquitination and degradation of various proteins. The UPS has many roles, including regulation of the cell cycle. To mediate these functions, there are many different types of E3s, each with different substrates. A major E3 system involved in oncogenesis is the Mdm2/MdmX system, which acts as a heterodimer to degrade the tumour suppressor, p53, responsible for inducing cell cycle arrest and/or apoptosis in cancer cells, as needed. Upon overexpression/hyperactivation through mutation, the Mdm2/MdmX system can promote carcinogenesis through increasing degradation of p53, preventing necessary cell cycle arrest/apoptosis in cancer cells. Methods: A literature review was conducted to synthesize and analyze research on Mdm2/MdmX E3 overexpression/hyperactivation, and the treatment options available for cancers in which overexpression/hyperactivation plays a role. Results: There are many types of mutations that may be present in cancer cells, however mutations leading to the inactivation of p53 are some of the most common. Inactivation of p53 can be achieved by direct gene mutation, or overexpression/hyperactivation of Mdm2/Mdmx. Current drugs target the expression of MdmX/Mdm2 or their binding interactions with p53. Inhibition of these interactions triggers apoptosis in cancer cells due to increased p53 activity. Therapies that have been developed to target the Mdm2/MdmX system include small molecule inhibitors such as Nutlins and MI compounds, as well as peptide drugs. Discussion: Although direct mutations of p53 are commonly found in cancer, mutated p53 is not a viable drug target, so instead many treatment options specifically target a dysregulated Mdm2/MdmX system. Future studies should investigate novel drug targets, minimization of side effects, and treatment in the presence of mutations to other DNA repair systems. Conclusion: This literature review aids in establishing an interdisciplinary perspective on the types of oncogenic mutations in the Mdm2/MdmX pathway, combining biochemical and mechanistic research with clinical applications and pharmacology, as well as identifying future drug targets involved in this system.