Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Abstract

The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

“…All these beneficial effects of JNJ-165 were reduced by the transfection of RXRβ siRNA, but not p53 siRNA. In line with our results, there is a notion that beyond the primary function of MDM2 to keep p53 under control, MDM2 has functions that are independent of p53 in vascular cells such as endothelial cells, vascular smooth cells and cardiomyocytes [ 16 ]. Moreover, the in vivo experiment in the present study for the first time showed that MDM2 inhibitor JNJ-165 alleviated the development of atherosclerosis and reversed mitochondrial damage and related inflammation in this process, along with the increased RXRβ protein expression in the aorta of mice.…”

“…MDM2 is involved in many important biological processes. In addition to its well-known tumorigenic characteristics by impacting p53, MDM2 is also reported to be involved in the pathophysiological events of the cardiovascular system [ 16 , 17 , 18 , 19 , 20 ]. Our previous study has indicated that MDM2 contributes to ox-LDL-induced activation of the TLR9/NF-κB pathway and NLRP3/caspase-1 inflammasome through modulation of mitochondrial damage in endothelial cells [ 21 ].…”

“…MDM2 is considered a hub protein due to its capacity to interact with more than 100 different partners and the list is continuously increasing [ 15 ]. Under different conditions, MDM2 interacts with different substrates to provide a key intermediary role in different signaling pathways [ 15 , 16 ]. For example, several studies uncovered the role of MDM2 in mitochondrial bioenergetics independently of p53 leading to decreased mitochondrial respiration, marked oxidative stress and DNA damage [ 32 , 33 , 34 ].…”

“…Functioning as an E3 ubiquitin ligase, murine double minute 2 (MDM2) targets various substrates for mono- and/ or poly-ubiquitination, thereby regulating their activities, for instance, by controlling their stability, conformation, and/or localization by proteasome-dependent degradation [ 15 ]. Dysregulated MDM2 is implicated in cardiovascular impairments [ 16 ]. For example, MDM2 is overexpressed in human atherosclerotic lesions [ 17 ].…”

Dynamic map illuminates Hippo to cMyc module crosstalk driving cardiomyocyte proliferation

“…However, our model predicted that it decreased DNA synthesis activity. MDM2 plays a diverse role in the cardiovascular systems, and studies to elucidate its interaction with upstream and downstream regulators are needed (Hauck et al, 2017; Lam & Roudier, 2019; Stanley-Hasnain et al, 2017). The majority of the incorrect predictions involved output responses for the polyploid phenotype.…”