TABLE 1.

Summary of the putative cardiovascular functions of upstream regulatory kinases for MDM2 discussed in this review.

Kinase	Sites phosphorylated	Effect on MDM2 function	Known or presumed cardiovascular function
DNA-PK	Ser17	Limits MDM2-TP53 interaction	Control of smooth muscle proliferation (Medunjanin et al., 2015; Kinoshita et al., 2017)
			Maintenance of endothelial cell quiescence (Mannell et al., 2010)
			Increased level of myocardial expression in dilated cardiomyopathy (Bartunek et al., 2002)
ERK1/2	Ser166 and Ser 186	Stabilizes MDM2, facilitates nuclear translocation	Alterations of the ERK related pathway are involved in cardiovascular pathogenesis (Muslin, 2008)
Akt/PKB	Ser166 and Ser 186	Stabilizes MDM2, limits self-ubiquitination and degradation, facilitates nuclear localization	Akt/PKB pathway is crucial regulator of cell survival, angiogenesis, vasodilation, metabolism in the cardiovascular system (Abeyrathna and Su, 2015)
Cyclin A/CDK2	Thr216	Promotes MDM2-TP53 interaction	Control of cell cycle in the cardiovascular system (Stanley-Hasnain et al., 2017)
GSK-3	Ser240 and Ser254	Limits MDM2-TP53 interaction, inhibition of TP53 ubiquitination and degradation	Regulates cardiac myocyte metabolism and controls cardiac hypertrophy (Potz et al., 2016; Takahashi-Yanaga, 2018)
ATM	Ser395	Reduces the capacity of MDM2 to facilitate the nuclear-cytoplasmic translocation and degradation of TP53	Control of pathological angiogenesis, involvement in atherosclerosis, insulin resistance and cardiac remodeling and sensing of β-adrenergic signals (Okuno et al., 2012; Espach et al., 2015)