p53 Regulation

Role of Mdmx in cancer development and cancer treatment

It has been well established that loss of function of the p53 tumor suppressor protein is a major step in the development of cancer. This can be obtained by direct mutation of the p53 gene, but also by alterations in p53 regulators and/or downstream targets. It has been established that the Mdm2 protein is an essential regulator of p53 during embryonic development.

Our group has identified the Mdmx protein, which is also an essential regulator of p53 during embryonic development in mice (Shvarts et al., 1996; Parant et al, 2001; Migliorini et al., 2002). Mdmx and Mdm2 are non-redundant critical inhibitors of p53 activity in normal cells.

Recent results of our group and others have shown that Mdmx functions as an oncogene in various types of tumors, including retinoblastoma, uveal- and cutaneous melanoma and Ewing Sarcoma.

In addition, we have elucidated at least part of the mechanism by which both Mdmx and Mdm2 are destabilized upon DNA damage, which is essential for proper activation of p53. Since several cancer drugs also elicit a DNA damage response expression and regulation of Mdmx in cancer can affect the efficacy of such drugs.

Comparison of the MDM2 and MDMX primary structure

Figure 1: Comparison of the MDM2 and MDMX primary structure. Several functional domains are highlighted. The p53-binding domain, Zn finger and RING finger (containing the Nucleolar Location Signal (NoLS)) are conserved. The percentage of identity between these domains is indicated. Although both MDM2 and MDMX contain an acidic domain, no significant conservation of primary amino acid sequence is found, and the acidic domain of MDMX is smaller compared to that of MDM2. Part of the MDMX amino acid sequence (338-407) is shown to better indicate the functional domains and modification sites. Serines (S) indicated in red are validated phosphorylation sites, whereas Lysines (K) indicated in blue are targets for SUMO-conjugation. NLS, Nuclear Localization Signal; NES, Nuclear Export Signal; DVPD, caspase-3 cleavage site.