The MDM2-p53 pathway: Multiple roles in kidney development

Samir S. El-Dahr, Sylvia Hilliard, Karam Aboudehen, Zubaida Saifudeen

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The molecular basis of nephron progenitor cell renewal and differentiation into nascent epithelial nephrons is an area of intense investigation. Defects in these early stages of nephrogenesis lead to renal hypoplasia, and eventually hypertension and chronic kidney disease. Terminal nephron differentiation, the process by which renal epithelial precursor cells exit the cell cycle and acquire physiological functions is equally important. Failure of terminal epithelial cell differentiation results in renal dysplasia and cystogenesis. Thus, a better understanding of the transcriptional frameworks that regulate early and late renal cell differentiation is of great clinical significance. In this review, we will discuss evidence implicating the MDM2-p53 pathway in cell fate determination during development. The emerging central theme from loss- and gain-of-function studies is that tight regulation of p53 levels and transcriptional activity is absolutely required for nephrogenesis. We will also discuss how post-translational modifications of p53 (e.g., acetylation and phosphorylation) alter the spatiotemporal and functional properties of p53 and thus cell fate during kidney development. Mutations and polymorphisms in the MDM2-p53 pathway are present in more than 50 % of cancers in humans. This raises the question of whether sequence variants in the MDM2 - p53 pathway increase the susceptibility to renal dysgenesis, hypertension or chronic kidney disease. With the advent of whole exome sequencing and other high throughput technologies, this hypothesis is testable in cohorts of children with renal dysgenesis.

Original languageEnglish (US)
Pages (from-to)621-627
Number of pages7
JournalPediatric Nephrology
Volume29
Issue number4
DOIs
StatePublished - Apr 2014

Bibliographical note

Funding Information:
The authors would like to thank the Tulane Hypertension and Renal Center of Excellence Molecular and Imaging Core. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK62550 and RO1DK56264 to SED and by National Institutes of Health National Center for Research Resources (NIH-NCRR) Center of Biomedical Research Excellence grant support P20RR017659 to ZS.

Keywords

  • MDM2
  • Nephrogenesis
  • Terminal differentiation
  • p53
  • p73

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