Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development

Abstract

The Mdm2 and Mdm4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p53 tumor suppressor protein and inhibit p53 activity. Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53. However, the phenotypes of Mdm2 and Mdm4-deficient mice suggest that Mdm2 and Mdm4 play nonoverlapping roles in regulating p53 activity during development, with Mdm2 regulating p53-mediated cell death and Mdm4 regulating p53-mediated inhibition of cell growth. Here, we describe complete rescue of Mdm4-deficient mice by expression of an Mdm2 transgene, and demonstrate that Mdm2 can regulate both p53-mediated apoptosis and inhibition of cell growth in the absence of Mdm4 in primary cells. Furthermore, deletion of Mdm4 enhances the ability of Mdm2 to promote cell growth and tumor formation, indicating that Mdm4 has antioncogenic properties when Mdm2 is overexpressed

MDMX: from bench to bedside

“…Indeed, Mdmx loss leads to a moderate increase in Mdm2 protein levels in vitro and an increase in Mdm2 transcription in vivo Francoz et al, 2006;Toledo et al, 2006). Note also that overexpression of an Mdm2 transgene rescues the embryonic lethality associated with Mdmx-deficiency (Steinman et al, 2005), indicating that high levels of Mdm2 compensate for Mdmx loss. Thus, increased Mdm2 levels might better compensate for Mdmx loss in specific cell types, which would represent an alternative to a more simplistic view of a tissuespecific function of Mdmx.…”

Limiting the power of p53 through the ubiquitin proteasome pathway

“…Mdm2 homodimers are formed at higher protein levels, and these dimers can polyubiquitinate p53. Perhaps this is the reason that Mdm2 transgenic mice can rescue lethality of Mdm4-null mice (Steinman et al 2005). Moreover, inactivation of Mdm2, but not Mdm4, leads to increased p53 levels in mice (Francoz et al 2006;Xiong et al 2006;Barboza et al 2008).…”

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

“…27,28 The stimulation of mdm2 transcription therefore complicates the interpretation of the results from mdm4 deficiency. In one particular example, overexpression of an mdm2 transgene rescues the embryonic lethality associated with mdm4 deficiency, 48 indicating that high levels of Mdm2 compensate for mdm4 loss. Thus, as an alternative to the simplistic view of tissue-specific function for Mdm4, increased Mdm2 levels might better compensate for mdm4 loss in specific cell types.…”