Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations That Prevent Modifications by DNA-damage-activated Kinases

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2009 Jul 4

PMID 19573810

Citations 57

Authors

Yunyuan V Wang

Mathias Leblanc

Mark Wade

Aart G Jochemsen

Geoffrey M Wahl

Affiliations

Soon will be listed here.

Abstract

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.

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