The International Journal of Biochemistry & Cell Biology
Signalling networks in focusPuzzling over MDM4–p53 network
Introduction
Murine Mdm4 (for transformed mouse 3T3 cell double minute 4, also Mdmx) and human ortholog MDM4 (also HDMX) have been identified as the closest analogues of Mdm2 (transformed mouse 3T3 cell double minute 2), the best-known inhibitor of p53 (Shvarts et al., 1996). In analogy to MDM2, MDM4 possesses a p53-binding domain (p53BD) encompassing approximately the first 100 aminoacids, and a C-terminus RING (really interesting new gene) finger region through which it interacts with MDM2 (Marine et al., 2007) (Fig. 1).
MDM2 inhibitory function revolves around the control of p53 transcriptional function and protein levels. Similarly, MDM4 has been characterized as inhibitor of p53 transcriptional function. Afterwards, activity of MDM4 on the control of p53 levels has emerged as well. However, at variance with MDM2, MDM4 does not possess ubiquitin ligase activity and exerts its function by cooperating with MDM2 (Wade and Wahl, 2009).
Recent studies have characterized supporting activities of MDM4 towards p53 stability and apoptotic function under stress conditions, leading to reconsider MDM4 as a multitalented regulator of p53 (Barboza et al., 2008, Mancini et al., 2009, Tsvetkov et al., 2009).
Section snippets
MDM4-mediated regulation of p53 under normal growth conditions
MDM4 regulates p53 primarily through physical association. P53BD is located at N-terminus of MDM4 and shows high sequence similarity to the relative domain of MDM2 (53.6% identity). In this domain, the p53-binding cleft is composed of hydrophobic residues that form three contiguous narrow pockets which host Phe19, Trp23, and Leu26 of the N-terminal transactivation domain of p53. Popowicz et al. (2008) first showed that the shape of the p53BD in the humanized zebra-fish MDM4 structure differs
MDM4-mediated regulation of p53 upon stress conditions
Whereas the role of MDM members in the inhibition of basal p53 function is well established, their function upon stress conditions is more complex. In response to stress, p53 becomes active executing its cellular gatekeeper functions. A crucial step in p53 activation is its de-repression by MDM proteins that leads to increased p53 transcriptional function and/or protein stability (Kruse and Gu, 2009). Recent data have hypothesized that MDM proteins, besides releasing their inhibition, play
Conclusions
MDM4 is a p53 inhibitor and as a consequence a bonafide potential oncogene. Accordingly, it cooperates with Rasv12 in neoplastic transformation (Marine et al., 2006) and the stable mutant form MDM4S3A accelerates Myc-induced lymphoma formation (Wang et al., 2009a). Moreover, its gene has been found amplified in various tumour histotypes (Wade and Wahl, 2009).
However, evidence is emerging that MDM4 is not only a p53 inhibitor. Upon stress, it contributes to p53 activation by stabilizing its
Acknowledgements
This work was supported by the Italian Association for Cancer Research (AIRC) and the Ministero della Salute. Olimpia Monti is a recipient of a FIRC fellowship. The authors regret that not all relevant reports could be cited due to reference number limitation.
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These authors contributed equally to this work.