Abstract
The MDM family proteins MDM2 and MDMX are two critical regulators of the p53 tumor suppressor protein. Expression of both proteins is necessary for allowing the embryonal development by keeping the activity of p53 in check. Upon stresses that need to activate p53 to perform its function as guardian of the genome, p53 has to be liberated from these two inhibitors. In this review, we will discuss the various mechanisms by which MDMX protein levels are downregulated upon various types of stress, including posttranslational modifications of the MDMX protein and the regulation of mdmx mRNA expression, including alternative splicing. In addition, the putative function(s) of the described MDMX splice variants, particularly in tumor development, will be discussed. Lastly, in contrast to common belief, we have recently shown the existence of a p53-MDMX feedback loop, which is important for dampening the p53-response at later phases after genotoxic stress.
Highlights
The tumor suppressor protein p53 is maintaining genome integrity following stress signals by either inducing a cell cycle arrest, allowing a complete checkup of the genome before resuming DNA replication, inducing senescence, or by stimulating apoptosis when the cell is beyond rescue [1]
It has been shown that p53 affects the metabolic switch which occurs in many tumors, in which energy is obtained by glycolysis rather than via oxidative phosphorylation [4]. p53 is activated by a plethora of stimuli, including DNA damage, hypoxia, and oncogene activation, the final outcome of the activation being very dependent on the strength and type of the stimulus and the type of targeted cell
One might argue that only a dimer/oligomer of MDM2/MDMX RING fingers can bind the E2; since MDMX cannot homodimerize, MDMX on its own is defective as a ubiquitin ligase
Summary
The tumor suppressor protein p53 is maintaining genome integrity following stress signals by either inducing a cell cycle arrest, allowing a complete checkup of the genome before resuming DNA replication, inducing senescence, or by stimulating apoptosis when the cell is beyond rescue [1]. Tissue-specific deletion of either the mdm gene or the mdmx gene showed differences between cell types for their dependency on MDM2 and MDMX to keep p53 in check. These mouse models have recently been discussed in two excellent reviews [9, 10]. Other conserved structures include the C-terminal RING finger domain, a Zn-finger and a central acidic region. No significant homo-oligomerization of MDMX could be found This deficiency could have strong implications for the function of MDMX (see below). Essential for p53 ubiquitination are both the MDM2 C-terminal region including
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