Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.
Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA-damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Myc-induced lymphomagenesis. These data demonstrate that Mdmx downregulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo.
Wang
Yunyuan V
YV
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Leblanc
Mathias
M
Wade
Mark
M
Jochemsen
Aart G
AG
Wahl
Geoffrey M
GM
D000818:Animals; D015139:Blotting, Southern; D003062:Codon / Q000235:genetics; D017124:Conserved Sequence; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D011995:Recombination, Genetic; D012694:Serine; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D003062:Codon; D016159:Tumor Suppressor Protein p53; D012694:Serine; D051736:Proto-Oncogene Proteins c-mdm2