Regulation of kidney development by the Mdm2/Mdm4–p53 axis

Abstract

While p53 activity is required for tumour suppression, unconstrained p53 activity on the other hand is detrimental to the organism, resulting in inappropriate cellular death or proliferation defects. Unimpeded p53 activity is lethal in the developing embryo, underlining the need for maintaining a tight control on p53 activity during this period. The critical role of the negative regulators of p53, Mdm2 and Mdm4, in vertebrate development came to light by fatal disruption of embryogenesis that was observed with Mdm2 and Mdm4 gene deletions in mice. Embryonic lethality was rescued only by superimposing p53 removal. Here we summarize the contribution of the Mdm2/Mdm4–p53 axis that occurs at multiple steps of kidney development. Conditional, cell type-specific deletions reveal distinct functions of these proteins in renal morphogenesis. The severe impact on the renal phenotype from targeted gene deletions underscores the critical role played by the Mdm2/Mdm4–p53 nexus on nephrogenesis, and emphasizes the need to monitor patients with aberrations in this pathway for kidney function defects and associated cardiovascular dysfunction.

TGF-β1/p53 signaling in renal fibrogenesis

“…The participation of MDM2 in fibrosis, however, is complex. MDM2 is a major regulator of p53 function, via inhibition of transcriptional activity, and stability by virtue of its role as a ligase [112]. While TGF-β1 induces p53 activation in vitro and in vivo, this growth factor also increases MDM2 expression in a p53-dependent manner establishing a feedback loop where p53 initiates expression of its negative regulator [54,112,113].…”

“…MDM2 is a major regulator of p53 function, via inhibition of transcriptional activity, and stability by virtue of its role as a ligase [112]. While TGF-β1 induces p53 activation in vitro and in vivo, this growth factor also increases MDM2 expression in a p53-dependent manner establishing a feedback loop where p53 initiates expression of its negative regulator [54,112,113]. Recent findings suggest that MDM2 also mediates fibroblast activation and renal interstitial fibrosis through a p53-independent pathway perhaps involving Notch I down-regulation [113].…”

Aquaporin 2 Expression in Human Fetal Kidney Development

“…The kidney develops from two sources: the metanephric mesoderm and the ureteric bud. During week 5 of development the metanephric mesoderm develops from the intermediate mesoderm, and the ureteric bud develops from the mesonephric duct [1,2,3,4]. At the beginning of week 6 the ureteric bud gives rise to the primitive renal pelvis.…”

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

“…Therefore, MDMX has been demonstrated as a promising but underutilized molecular target for cancer therapy. Over the past few years, there have been several review articles on the roles of MDMX in cancer and development (15)(16)(17)(18)(22)(23)(24), MDMX isoforms (25), inhibitors of p53-MDM2/MDMX interactions (26)(27)(28)(29), as well as mouse modeling of MDMX (12). In the present review, we will discuss the MDMX protein structure and the role of MDMX in the p53-MDM2/MDMX loop but mainly focus on the clinical relevance of MDMX in cancer, current MDMX-targeting strategies and related MDMX inhibitors, and other potential strategies for developing new MDMX inhibitors.…”