The p53 Tumor Suppressor Causes Congenital Malformations in Rpl24-Deficient Mice and Promotes Their Survival

Abstract

Hypomorphic mutation in one allele of ribosomal protein l24 gene (Rpl24) is responsible for the Belly Spot and Tail (Bst) mouse, which suffers from defects of the eye, skeleton, and coat pigmentation. It has been hypothesized that these pathological manifestations result exclusively from faulty protein synthesis. We demonstrate here that upregulation of the p53 tumor suppressor during the restricted period of embryonic development significantly contributes to the Bst phenotype. However, in the absence of p53 a large majority of Rpl24^Bst/+ embryos die. We showed that p53 promotes survival of these mice via p21-dependent mechanism. Our results imply that activation of a p53-dependent checkpoint mechanism in response to various ribosomal protein deficiencies might also play a role in the pathogenesis of congenital malformations in humans.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Stefano Fumagalli for his useful discussions; Jacques Montagne, Mario Pende, and Nick Pullen for their comments; Jonathan Ashwell and Ivan Dikic for reading the manuscript; Tihomila Bušić and Miljana Uzelac for technical assistance; and Mladen Petrovečki for statistical analysis. We are grateful to George Thomas and Davor Solter for their continuous support of our work.

This study was supported by grants from the Ministry of Science, Education, and Sports of Croatia.