Mdm proteins: critical regulators of embryogenesis and homoeostasis

Abstract

Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53; hence, this relationship is the focus of many cancer-related studies. A multitude of experiments across various developmental stages have been conducted to explore the tissue-specific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germline or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethality. Mdm2 loss is often more deleterious than loss of its homologue Mdm4. All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evolving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the cell-specific level.

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

“…In addition, we provide evidence that p53EE, similar to other p53 mutants, interferes with Nrf2 transcriptional activity, which is critical not only for ROS defense, but also for the respiratory function of mitochondria, their biogenesis, and integrity (Dinkova-Kostova & Abramov, 2015). However, deregulated p53 can cause embryonic lethality by multiple pathways including apoptosis, ferroptosis, or cell growth arrest (Jiang et al, 2015;Moyer et al, 2017). Nevertheless, we cannot formally exclude that p53EE under conditions of maximal stimulation induces pro-apoptotic target genes to a degree that is below our detection limit.…”

“…And indeed, it was shown that a single hypomorphic Trp53 neo allele (Trp53 neo/À ) that shows~7% activity is compatible with Mdm2 À/À embryonic development, whereas Trp53 neo/neo homozygosity, yielding~16% activity, already triggers embryonic lethality (Wang et al, 2011). However, deregulated p53 can cause embryonic lethality by multiple pathways including apoptosis, ferroptosis, or cell growth arrest (Jiang et al, 2015;Moyer et al, 2017). Whether Trp53 neo/neo ;Mdm2 À/À embryos die by apoptosis was not reported.…”

The role of p53 in developmental syndromes

“…In these mouse strains, p53 hyperactivation has been achieved through mutations in Trp53 , the gene encoding p53, or mutations in Mdm2 or Mdm4 , which encode the two main negative regulators of p53 that act cooperatively to inhibit the transactivation domains of p53 and to target p53 for ubiquitin-mediated degradation (Figure 1A and B) (Perry, 2010). These mouse strains display a range of developmental phenotypes, the most striking of which occur in Mdm2- and Mdm4- null mice, which exhibit p53-dependent lethality by embryonic day 5.5 (E5.5) and E8.5, respectively (Figure 1B and C) (Jones et al, 1995; Montes de Oca Luna et al, 1995; Parant et al, 2001; Chavez-Reyes et al, 2003; Moyer et al, 2017). Mouse strains with milder levels of p53 hyperactivation—due to only partial loss of Mdm2 or Mdm4, or due to the expression of mutant p53 proteins with modestly enhanced stability or activity—survive beyond early embryogenesis and display defects only at later developmental stages (Figure 1B and C).…”

Mouse modelling of the MDM2/MDMX−p53 signalling axis

“…In the following section, we will review work from whole body MDM2 and MDMX knockout studies. For a more comprehensive discussion of tissue-specific deletion studies, please refer to an accompanying review by Guillermina Lozano and her colleagues ( Moyer et al, 2017 ) in this special issue.…”