References
Query Results -- Details
MGI Accession ID: MGI:3815232
J Number: J:140998
Other Accession IDs:
Title: Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis.
Authors: El-Dahr SS; Aboudehen K; Dipp S
Journal: Am J Physiol Renal Physiol
Volume: 295
Issue: 5
Date: 2008 Nov
Year: 2008
Pages: F1404-13
Review Status: Peer Reviewed
Abstract:
A physiological cross talk operates between the tumor suppressor protein p53 and the bradykinin B(2) receptor (BdkrB2) during renal organogenesis. Thus, although BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 is required to restrict p53 proapoptotic activity. We previously demonstrated that BdkrB2(-/-) embryos exposed to gestational salt stress develop renal dysgenesis as a result of p53-mediated apoptosis of nephron progenitors and repression of the terminal differentiation program. Compared with wild-type kidneys, BdkrB2(-/-) express abnormally high levels of the Checkpoint kinase (Chk1), which activates p53 via Ser(23) phosphorylation. To define the functional relevance of p53(S23) phosphorylation, we generated a compound strain of BdkrB2(-/-) mice harboring a homozygous Ser(23)-to-Ala (S23A) mutation in the p53 gene by crossing BdkrB2(-/-) with p53(S23A) knockin mice. Unlike salt-stressed BdkrB2(-/-) pups, which exhibit renal dysgenesis, homozygous S23A;BdkrB2(-/-) littermates are protected and have normal renal development. Heterozygous S23A;BdkrB2(-/-) mice have an intermediate phenotype. The p53-S23A substitution was associated with amelioration of apoptosis and restored markers of nephrogenesis and tubulogenesis. Real-time quantitative RT-PCR of terminal differentiation genes demonstrated that the S23A substitution restored normal expression patterns of aquaporin-2, Na-Cl cotransporter, Na-K-2Cl cotransporter, Na-bicarbonate cotransporter, and Sglt1. We conclude that p53 phosphorylation on Ser(23) is an essential step in the signaling pathway mediating the susceptibility of BdkrB2(-/-) mutants to renal dysgenesis.
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