Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency. Am J Physiol Regul Integr Comp Physiol 2005 Apr;288(4):R1038-45
Date
11/26/2004Pubmed ID
15563574DOI
10.1152/ajpregu.00701.2004Scopus ID
2-s2.0-15544369602 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
Severe uteroplacental insufficiency causes cerebral apoptosis in the fetus. Moderate uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and increases the risk of postnatal neurological morbidity. In the rat, uteroplacental insufficiency and IUGR affect cerebral gene expression of Bcl-2 and predispose the newborn IUGR rat toward cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the proapoptotic protein Bax, is regulated by p53. p53 also induces MDM2 transcription, which functions to limit further p53-induced apoptosis. The predisposition of the IUGR fetus toward cerebral apoptosis suggests that the p53-MDM2 "functional" circuit may be perturbed in the newborn IUGR rat brain. We hypothesized that MDM2 cerebral expression does not increase in response to increased p53 expression or increased levels of phospho-p53 (Ser15), an activated form of p53. To prove this hypothesis, we induced IUGR through bilateral uterine ligation of the pregnant rat. Uteroplacental insufficiency significantly increased p53 mRNA, total p53 protein, and phospho-p53 (Ser15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were localized to the CA1 region of the hippocampus, the subcortical and periventricular white matter, and the amygdala of the IUGR rat brain. In contrast, uteroplacental insufficiency decreased cerebral MDM2 mRNA and phospho-MDM2 (Ser166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the newborn IUGR rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus toward perinatal and long-term neurodevelopmental morbidities.
Author List
Ke X, McKnight RA, Wang ZM, Yu X, Wang L, Callaway CW, Albertine KH, Lane RHMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Base Sequence
Brain
Brain Chemistry
DNA, Complementary
Female
Fetal Growth Retardation
Gene Expression
Immunoblotting
Immunohistochemistry
In Situ Nick-End Labeling
Nuclear Proteins
Placental Insufficiency
Pregnancy
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
RNA, Messenger
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
