A transactivation-deficient mouse model provides insights into Trp53 regulation and function

Nat Genet. 2000 Sep;26(1):37-43. doi: 10.1038/79152.


The gene Trp53 is among the most frequently mutated and studied genes in human cancer, but the mechanisms by which it suppresses tumour formation remain unclear. We generated mice with an allele encoding changes at Leu25 and Trp26, known to be essential for transcriptional transactivation and Mdm2 binding, to enable analyses of Trp53 structure and function in vivo. The mutant Trp53 was abundant, its level was not affected by DNA damage and it bound DNA constitutively; however, it showed defects in cell-cycle regulation and apoptosis. Both mutant and Trp53-null mouse embryonic fibroblasts (MEFs) were readily transformed by oncogenes, and the corresponding mice were prone to tumours. We conclude that the determining pathway for Trp53 tumour-suppressor function in mice requires the transactivation domain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Apoptosis / genetics
  • DNA Damage / drug effects
  • Dactinomycin / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, p53*
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Neoplasm Transplantation
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Transcriptional Activation*
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53* / chemistry
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism


  • Nucleic Acid Synthesis Inhibitors
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Dactinomycin