DNA Damage-induced MDMX Degradation Is Mediated by MDM2

Abstract

Although genetic studies have demonstrated that MDMX is essential to maintain p53 activity at low levels in non-stressed cells, it is unknown whether MDMX regulates p53 activation by DNA damage. We show here that DNA damage-induced p53 induction is associated with rapid down-regulation of the MDMX protein. Significantly, interference with MDMX down-regulation results in the suppression of p53 activation by genotoxic stress. We also demonstrate that DNA damage-induced MDMX reduction is mediated by MDM2, which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation.

MdmX is a substrate for the deubiquitinating enzyme USP2a

“…As well as promoting ubiquitination of p53, Mdm2 promotes the ubiquitination and proteasomal degradation of MdmX (Kawai et al, 2003). In this study, we observed that ectopically expressed USP2a deubiquitinates MdmX and consequently inhibits Mdm2-mediated MdmX degradation.…”

“…It has been shown that some p53-activating stresses result in a decrease in the stability of MdmX and consequently a decrease in MdmX protein levels (Kawai et al, 2003;Gilkes et al, 2006). To investigate whether changes in USP2a expression could be involved in regulation of MdmX following stress NTERA-2 cells were treated with 20 mM cisplatin for between 2 and 10 h as indicated (Figure 5a).…”

“…MdmX is itself a substrate for the E3 ubiquitin ligase activity of Mdm2 (Kawai et al, 2003). Mdm2 ubiquitinates MdmX and promotes its proteasomal degradation.…”

“…Mdm2 ubiquitinates MdmX and promotes its proteasomal degradation. Upon DNA damage MdmX is rapidly degraded via a Mdm2-dependent mechanism (Kawai et al, 2003). In addition, DNA damage destabilizes Mdm2 by enhancing its proteasomal degradation (Stommel and Wahl, 2004).…”

Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP)

“…MDM2's inherent instability stems from its capacity to self-ubiquitylate (Kawai et al, 2003). As G3BP2 overexpression suppressed MDM2-mediated p53 ubiquitylation, we wanted to know if G3BP2 could also interfere with MDM2 auto-ubiquitylation.…”