MDMX under stress: the MDMX-MDM2 complex as stress signals hub

The evolutionary conservation of p53 across invertebrate and vertebrate species underscores its prominence in preserving cellular fitness and tissue function in multicellular organisms. p53 contributes to the maintenance of cellular homeostasis chiefly by controlling the expression of numerous genes in response to intra- and extra-cellular stress cues, hence representing a central element of the stress-response and cell fate decision process. In order to preserve their fitness in an energetically sensible way, cells have to constantly make cost-effective decisions that range between survival and death. To prevent and repair damages that can threaten their genome stability and the integrity of other essential structures, cells must sense cellular damage and promptly activate an appropriate response, such as cell cycle arrest, DNA repair or, if the damage is more severe, apoptosis. However, living cells are constantly exposed to an intrinsic level of stress caused by normal processes like cycling and division. Arresting the cell cycle or inducing programmed cell death in response to these transient and mild stresses would be energetically insensible. Therefore, to maintain their homeostasis and fitness, cells have to size their stress response to the perturbation that triggered it. Similarly, cells exposed to growth promoting stimuli need to be able to ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals. In order to do this, one of the restriction points they have to bypass is represented by p53-controlled anti-proliferative genes, which need to be downregulated in order for the cells to commit to cell cycle progression (1). In this context, it is essential for the cells and especially for actively proliferating cells to modulate the function and stability of p53, given its role as guardian of the cellular homeostasis