Targeted deletion of p73 in mice reveals its role in T cell development and lymphomagenesis

PLoS One. 2009 Nov 11;4(11):e7784. doi: 10.1371/journal.pone.0007784.

Abstract

Transcriptional silencing of the p73 gene through methylation has been demonstrated in human leukemias and lymphomas. However, the role of p73 in the malignant process remains to be explored. We show here that p73 acts as a T cell-specific tumor suppressor in a genetically defined mouse model, and that concomitant ablation of p53 and p73 predisposes mice to an increased incidence of thymic lymphomas compared to the loss of p53 alone. Our results demonstrate a causal role for loss of p73 in progression of T cell lymphomas to the stage of aggressive, disseminated disease. We provide evidence that tumorigenesis in mice lacking p53 and p73 proceeds through mechanisms involving altered patterns of gene expression, defects in early T cell development, impaired apoptosis, and the ensuing accumulation of chromosomal aberrations. Collectively, our data imply that tumor suppressive properties of p73 are highly dependent on cellular context, wherein p73 plays a major role in T cell development and neoplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Chromosome Aberrations
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • Gene Deletion*
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Genetic Predisposition to Disease
  • Lymphoma / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics*
  • Nucleic Acid Hybridization
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics*

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • TP73 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins