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First published online January 24, 2007
doi: 10.1242/10.1242/jcs.03362

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MDMX: from bench to bedside

¹ Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, B-9052 Ghent, Belgium
² Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA
³ Department of Molecular and Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

View larger version (20K): [in this window] [in a new window]   Fig. 1. Comparison of the MDM2 and MDMX primary structures. Several functional domains are highlighted. The p53-binding domain, zinc (Zn) finger and RING finger [containing the nucleolar location signal (NoLS)] are conserved. The percentage identity shared between these domains is indicated. Although both MDM2 and MDMX contain an acidic domain, no significant conservation of amino acid sequence is found, and the acidic domain of MDMX is smaller than that of MDM2. Part of the MDMX amino acid sequence (338-407) is shown to 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. DVPD, caspase-3 cleavage site; NES, nuclear export signal; NLS, nuclear localization signal.

View larger version (25K): [in this window] [in a new window]   Fig. 2. A model for cooperative control of the p53 pathway by Mdm2 and Mdmx. In the absence of stress signals, the primary function of Mdm2 is to maintain p53 at low levels, whereas Mdmx contributes to the overall inhibition of p53 independently of Mdm2. Mdmx inhibits p53 transcriptional activity, whereas the contribution of Mdm2 to the regulation of p53 transcriptional activity per se is still unclear and a matter of debate. The role of Cop-1 and Pirh2 in the regulation of p53 levels and activity in vivo is unclear, but recent data suggest that, if they participate in the regulation of this pathway, they can only do so in an Mdm2-dependent manner. See text for details.

View larger version (27K): [in this window] [in a new window]   Fig. 3. Interactions between Rb, MDMX and p53 during retinoblastoma formation. (A) Biallelic inactivation of the RB1 gene is the initiating oncogenic event in retinoblastoma. As a consequence, the activity of transcription factors of the E2F family is unleashed, leading to increased S-phase entry and induction of ARF expression. ARF is induced in response to oncogenic stress and a direct E2F3a transcription target. ARF functions as an Mdm2 antagonist and therefore activates the p53 pathway. High ARF expression was indeed recently detected in RB1-deficient retinoblasts and, as a consequence, a high proportion of these cells undergo p53-mediated apoptosis. (B) The p53 pathway is suppressed during the formation of retinoblastoma and the majority of tumors inactivate this pathway through selective amplification and/or overexpression of MDMX.