Regulation of p53: a collaboration between Mdm2 and MdmX

Abstract

p53 plays an important role in the regulation of the cell cycle, DNA repair, and apoptosis and is an attractive cancer therapeutic target. Mdm2 and Mdmx are recognized as the main p53 negative regulators. Although it is still unknown why Mdm2 and Mdmx both are required for p53 degradation, a model has been proposed whereby these two proteins function independent of one another; Mdm2 acts as an E3 ubiquitin ligase that catalyzes the ubiquitination of p53 for degradation, whereas Mdmx inhibits p53 by binding to and masking the transcriptional activation domain of p53, without causing its degradation. However, Mdm2 and Mdmx have been shown to function collaboratively. In fact, recent studies have pointed to a more important role for an Mdm2/Mdmx co-regulatory mechanism for p53 regulation than previously thought. In this review, we summarize current progress in the field about the functional and physical interactions between Mdm2 and Mdmx, their individual and collaborative roles in controlling p53, and inhibitors that target Mdm2 and Mdmx as a novel class of anticancer therapeutics.

p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3

“…12,13 Alternatively, if the DNA damage sustained is beyond repair, p53 is capable of initiating apoptosis. However, if this gate keeper of the cell cycle is taken out of the cell fate equation, then the resulting effects could be disastrous for cellular homeostasis and result in tissue malignancies.…”

“…When MDM2 is prevented from sequestering p53 to the cytoplasm, p53 is capable of translocating to the nucleus more readily and is able to promote transcription. [10][11][12][13] This action places the treated cells in a lysis buffer (GLB) (20 mM Tris pH 7.5, 137 mM NaCl, 5 mM EDTA, 1% Triton X-100, 15% glycerol) plus protease (10 μg/ mL leupeptin, 10 μg/mL aprotinin, 1 mM phenylmethylsulfonyl fluoride) and phosphatase (1 mM sodium orthovanadate, 1 mM EGTA, 10 mM sodium fluoride, 1 mM tetrasodium pyrophosphate, 100 μM β-glycerophosphate) inhibitors, vigorously shaking at 4°C for 15 min and centrifugated for 15 min at 14,000 RPM at 4°C. Resultant supernatants were collected and stored at -80°C until ready for use.…”

“…The proteosomal degradation of p53 is controlled by the E3 ubiquitin ligase, murine double minute-2 (MDM2). [10][11][12][13] When cell homeostasis is disrupted, phosphorylation of p53 and MDM2 by a series of kinases (e.g., ATR, ATM, CHK1, CHK2) leads to the stabilization and nuclear translocation of p53. 14,15 Dimerization of p53 molecules leads to the formation of functional tetramers that associate with p53 consensus sequences [5'-PuPuPuC(A/T) (T/A)GPyPyPy-3'] to promote gene expression.…”

Effects of p53 Codon 72 and MDM2 SNP309 Polymorphisms on Gastric Cancer Risk among the Iranian Population

“…MDM2 (murine double minute 2) was discovered on double minute chromosomes in a derived cell line of NIH-3T3 cells (Fakharzadeh et al, 1991;Momand et al, 1992). MDM2, as a p53 target gene, is part of E3 ubiquitin ligases family that includes a RING [really interesting new gene] domain and for p53 degradation act as the major E3 ubiquitin ligase (Pei et al, 2012). The MDM2 protein binds to p53 and regulates that by changing its location, stability and activity (Poyurovsky and Prives, 2006).…”

Molecular dynamics of the full-length p53 monomer

“…37 This results in significant changes in its functional properties as a transcription factor. [38][39][40][41][42][43] As a consequence of the p53 isoforms function as a transcription factor and its involvement in DNA damage, it is evident that the status of p53 plays a crucial role in cancer progression [44][45][46][47][48][49][50][51][52] as well in different physiological 2 and anticancer responses. 42 In fact, p53 is frequently mutated in cancer, resulting in novel "gain-of-function"effects.…”