Uteroplacental Insufficiency Increases P53 Phosphorylation Without Triggering the P53-mdm2 Functional Circuit Response in the Iugr Rat Kidney.
From: University of Utah School of Medicine, Department of Pediatrics, Division of Neonatology, PO Box 581289, Salt Lake City, UT 84158, USA. mariana.baserga@hsc.utah.edu
American journal of physiology. Regulatory, integrative and comparative physiology
- Publish Date: Aug 2006
- ISSN: 0363-6119
- Volume: 291
- Issue: 2
- Pages: R412-8
- Medium: Print
- Language: English
- Citation (JAMA): Baserga Mariana, Hale Merica A, Ke Xingrao, et al. Uteroplacental Insufficiency Increases P53 Phosphorylation Without Triggering the P53-mdm2 Functional Circuit Response in the Iugr Rat Kidney.. Am. J. Physiol. Regul. Integr. Comp. Physiol. Aug 2006;291:R412-8
Abstract
Uteroplacental insufficiency (UPI) leads to intrauterine growth restriction (IUGR), which predisposes infants toward renal insufficiency early in life and increases the risk of kidney-related adult morbidities, such as hypertension. This compromised in utero environment has been demonstrated to impair nephrogenesis, as evidenced by a reduced nephron endowment in humans and in rats rendered IUGR by UPI. Concordantly, we have observed that IUGR rats have increased kidney p53 protein levels associated with increased apoptosis. Several factors can regulate p53 gene expression and activity, including posttranslational modifications and protein-protein interactions in the cell. Among these, two important mechanisms are 1) phosphorylation of the amino terminal serine 15 [phospho-p53 (Ser15)], which increases p53 stability and apoptotic activity, and 2) the murine double-minute (MDM2) functional circuit that limits further p53-induced apoptosis by promoting proteosomal degradation of p53. We hypothesize that UPI induces an increase in phospho-p53 (Ser15) in association with an absent MDM2 response, predisposing the kidney to increased apoptosis. To test our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. UPI significantly increased phospho-p53 (Ser15), as well as ataxia teleangiectasia-mutated kinase/A-T-related kinase and dsDNA-activated protein kinase kinase levels, which induce phosphorylation of p53. In contrast, UPI induced no increase in kidney MDM2 mRNA and protein levels in IUGR pups. We conclude that among multiple mechanisms that affect nephrogenesis, UPI induces an increase in p53 phosphorylation without a corresponding increase in MDM2 expression, and we speculate that this response may contribute to the increased apoptosis previously described in the IUGR kidney.
Mesh Headings (Keywords): Animals, Apoptosis, Female, Fetal Growth Retardation, Kidney, Phosphorylation, Placental Circulation, Placental Insufficiency, Pregnancy, Protein Kinases, Proto-Oncogene Proteins c-mdm2, Rats, Rats, Sprague-Dawley, Tumor Suppressor Protein p53
Check for Full Text / PubMed Unique Identifier (PMID): 16914427
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.