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

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.

RETRACTED ARTICLE: Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

“…We examined whether Nrf2 nuclear translocation confers cytoprotection against oxidative stress by tumor suppressor degradation. Diverse signaling pathways have been established in mammalian cells to regulate expression of tumor suppressor Rb and p53 to improve cell survival pathway 52 – 54 . Mdm2 is an E3 ubiquitin ligase that promotes p53 ubiquitination at several lysine residues, leading to its proteosomal degradation 54 .…”

“…The loss of Rb function can also occur through the mutation in the Rb gene itself, hyper methylation of Rb promoter, bindings of viral proteins such as NS5B protein of HCV, E7 of the papilloma virus or E1A protein of adenovirus or post-transcriptional modification with tumor associated kinase activity 72 . Phosphorylation is also another well-characterized mechanism involved in Rb inhibition during cell cycle control, suggesting that Rb function can be inhibited by a wide variety of mechanisms 52 . In this study, we provide here another potential novel ER-stress related mechanism controlling Rb degradation through Mdm2 during HCV infection that leads to hepatocellular proliferation and chromosomal instability and HCC development ( Fig.…”

Targeting the NFAT1-MDM2-MDMX Network Inhibits the Proliferation and Invasion of Prostate Cancer Cells, Independent of p53 and Androgen

“…The murine double minute (MDM) oncogene family, consisting of MDM2 and MDMX, has been demonstrated to be a promising molecular target for the prevention and treatment of various types of human cancer, including prostate cancer ( Burgess et al, 2016 ; Karni-Schmidt et al, 2016 ; Lemos et al, 2016 ). MDM2 and MDMX are well characterized as negative regulators of the tumor suppressor p53 and have been proven to contribute to cancer initiation, progression, and metastasis, as well as the resistance to chemotherapy ( Hernandez-Monge et al, 2016 ; Karni-Schmidt et al, 2016 ). The binding of the RING domains of MDM2 and MDMX are pivotal for inhibiting p53 ( Huang et al, 2011 ; Pant et al, 2011 ).…”

Advanced Glycation End Products Increase MDM2 Expression via Transcription Factor KLF5

“…MDM2 can directly interact with p53 through the N-terminal regions and promote p53 proteasomal degradation in the cytoplasm [ 37 , 38 ]. Specifically in colon cancer, increases in MDM2 protein expression and gene amplification are observed [ 12 , 39 ], which is associated with increased colorectal cancer risk and can be used as a prognostic marker [ 33 ]. Knockdown of MDM2 enhances the efficacy of cisplatin-based chemotherapy in vitro and in vivo [ 40 ] as well as radiotherapy [ 41 ].…”

“…MDM2 is an oncogene, the amplification and overexpression of which are linked to progression and poor prognosis of different cancers. It can bind directly to cancer suppressors p53 and Rb to promote their inactivation and/or degradation [ 12 ].…”