Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency.
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.
Ke
Xingrao
X
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, 30 North 1900 East, Rm. 2A100, Salt Lake City, UT 84132-2202, USA.
McKnight
Robert A
RA
Wang
Zheng-Ming
ZM
Yu
Xing
X
Wang
Laiyi
L
Callaway
Christopher W
CW
Albertine
Kurt H
KH
Lane
Robert H
RH
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001483:Base Sequence; D001921:Brain / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010927:Placental Insufficiency / Q000503:physiopathology*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2