Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wang, YV; Leblanc, M; Wade, M; Jochemsen, AG; Wahl, GM

Published Date

  • July 2009

Published In

Volume / Issue

  • 16 / 1

Start / End Page

  • 33 - 43

PubMed ID

  • 19573810

Pubmed Central ID

  • 19573810

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

International Standard Serial Number (ISSN)

  • 1535-6108

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2009.05.008

Language

  • eng