Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB

Jesús Hernández-Monge,Adriana Berenice Rousset-Roman,Ixaura Medina-Medina,Vanesa Olivares-Illana

doi:10.18632/genesandcancer.120

Jesús Hernández-Monge, Adriana Berenice Rousset-Roman + Show 2 more

Open Access

https://doi.org/10.18632/genesandcancer.120

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Journal: Genes & Cancer	Publication Date: Oct 7, 2016
Citations: 35	License type: cc-by

Affiliation: Autonomous University of San Luis Potosí

Abstract

The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX. Under genotoxic stress conditions, both become positive regulators of p53. The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation. MDM2 and MDMX are also being revealed as effective regulators of the RB protein. MDM2 is able to degrade RB by two different mechanisms, that is, by ubiquitin dependent and independent pathways. MDMX enhances the ability of MDM2 to bind and degrade RB protein. However, MDMX also seems to stabilize RB through interaction and competition with MDM2. Here, we will contextualize the findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB.

Highlights

The p53 and retinoblastoma (RB) proteins are two key tumor suppressors
We will contextualize the findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB
Mutations in one or both are found in all human cancer tumors and both have been extensively studied as potential therapeutic targets in drug development programs. p53 is a transcription factor in which converge many cellular stress pathways such as oncogene activation, hypoxia, DNA damage, and endoplasmic reticulum stress, to induce different biological cell responses such as cell cycle arrest in G1 or G2, DNA repair, senescence, or even apoptosis [1]

Summary

Introduction

The p53 and retinoblastoma (RB) proteins are two key tumor suppressors. Mutations in one or both are found in all human cancer tumors and both have been extensively studied as potential therapeutic targets in drug development programs. p53 is a transcription factor in which converge many cellular stress pathways such as oncogene activation, hypoxia, DNA damage, and endoplasmic reticulum stress, to induce different biological cell responses such as cell cycle arrest in G1 or G2, DNA repair, senescence, or even apoptosis [1]. The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation. MDM2 is able to degrade RB by two different mechanisms, that is, by ubiquitin dependent and independent pathways.

Results

Conclusion