title: A novel pathological role of p53 in kidney development revealed by gene-environment interactions.
abstract: Gene-environment interactions are implicated in congenital human disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Previously, our laboratory demonstrated that gestational salt stress of bradykinin B(2) receptor (B(2)R)-null mice induces renal dysgenesis and early death of the offspring. In contrast, salt-stressed B(2)R +/+ or +/- littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B(2)R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B(2)R-/- kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser(20) p53 were induced. We tested the hypothesis that p53 mediates repression of E-cadherin gene expression and is causally linked to the renal dysgenesis. Genetic crosses between B(2)R -/- and p53+/- mice revealed that germline reduction of p53 gene dosage rescues B(2)R-/- mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, gamma-irradiation induces repression of E-cadherin gene expression in p53+/+ but not -/- cells. In transient transfection assays, p53 repressed human E-cadherin promoter-driven reporter activity, whereas a mutant p53, which cannot bind DNA, did not. Functional promoter analysis indicated the presence of a p53-responsive element in exon 1, which partially mediates p53-induced repression. Chromatin immunoprecipitation assays revealed that p53 inhibits histone acetylation of the E-cadherin promoter. Treatment with a histone deacetylase inhibitor reversed both p53-mediated promoter repression and deacetylation. In conclusion, this study demonstrates that gene-environment interactions cooperate to induce congenital defects through p53 activation.
authors.affiliation: Department of Pediatrics, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Fan
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Harrell
authors.forename: Susana
authors.initials: S
authors.lastname: Dipp
authors.forename: Zubaida
authors.initials: Z
authors.lastname: Saifudeen
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011494:Protein Kinases / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D012965:Sodium Chloride / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D015820:Cadherins; D043782:Receptor, Bradykinin B2; D016159:Tumor Suppressor Protein p53; D012965:Sodium Chloride; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse