MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Abstract

The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.

Highly Water‐Soluble Cyclopentadienyl and Indenyl Molybdenum(II) Complexes – Second Generation of Molybdenum‐Based Cytotoxic Agents

“…[19] All the compounds under the study (15)(16)(17)(18)(19)(20)(21)(22)(23) are highly active against both cell lines. Their IC50 values are much lower than reported for DDP, see Table 3.…”

“…This behavior seems to be similar to DDP, which mechanism of action has been described in literature. [20,21] After the purine bases to the DNA are damaged by DDP, the inner pathway activation of apoptosis in tumor cell is induced. Beside the inner induction (mitochondrial pathway) the FasL mRNA expression is induced.…”

Updates on p53: modulation of p53 degradation as a therapeutic approach

“…In addition, the interaction between the transactivation domain of p53 and the N-terminal domain of Mdm2 is also known to modulate the interaction between an acidic domain of Mdm2 and the DNA-binding domain of p53; whether this interaction (a) extends to interactions with Mdm4 and (b) can be targeted for increasing the stability of WT p53, remains to be seen. A dynamic model integrating the specific and complementary roles of Mdm2 and Mdm4 has been proposed (Toledo and Wahl, 2007). These interactions are modulated by a range of post-translational modifications such as phosphorylation, acetylation, ubiquitination, sumoylation, neddylation and glycosylation and provide an avenue for further development of inhibitors based on mechanistic details of how these modifications stabilise/ destabilise the p53 -Mdm2/Mdm4 system.…”

“…Thus, for example, p53À/À:Mdm2À/À mice are viable, while p53 þ /À:Mdm2À/À mice are not and the same is seen for Mdm4À/À mice. This has naturally led to an intense exploration of WT p53 activation by downregulating Mdm2 function (Coutts and La Thangue, 2007;Toledo and Wahl, 2007;Vassilev, 2007). The three main approaches include repressing the expression of Mdm2, inhibiting the p53 -Mdm2 interaction and blocking the ubiquitin ligase activity of Mdm2.…”

MdmX is a substrate for the deubiquitinating enzyme USP2a

“…In both cases this lethality can be rescued in a p53-null background (Montes de Oca Luna et al, 1995;Parant et al, 2001;Finch et al, 2002;Migliorini et al, 2002). Targeting Mdm2 and/or MdmX is an approach to activate wild-type p53 for cancer therapy (Marine et al, 2007;Toledo and Wahl, 2007;Wade and Wahl, 2009). Suppression of Mdm2 causes cell cycle arrest and in some cases apoptosis in tumourderived cells expressing wild-type p53 (Vassilev, 2007).…”