Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background

Neil J Toft, Lucy J Curtis, Owen J Sansom, Andrea L Leitch, Andrew H Wyllie, Hein te Riele, Mark J Arends, Alan R Clarke

Research output: Contribution to journalArticlepeer-review

Abstract

In colorectal tumorigenesis, loss of function of the mismatch repair genes is closely associated with genomic instability at the nucleotide level whereas p53 deficiency has been linked with gross chromosomal instability. We have addressed the contribution of these two forms of genetic instability to tumorigenesis using mice mutant for Msh2 and p53. As previously reported, deficiency of both genes leads to rapid lymphomagenesis Here we show that heterozygosity for p53 also markedly reduces survival on an Msh2 null background. We characterized the patterns of genomic instability in a small set of tumours and showed that, as predicted p53 deficiency predisposes to aneuploidy and Msh2 deficiency leads to microsatellite instability (MSI). However, heterozygosity for p53 in the absence of Msh2 resulted in increased MSI and not aneuploidy. This implied role for p53 in modulating MSI was confirmed using a large cohort of primary fibroblast clones. The differences observed were highly significant (P
Original languageEnglish
Pages (from-to)6299-306
Number of pages8
JournalOncogene
Volume21
Issue number41
DOIs
Publication statusPublished - 12 Sep 2002

Keywords

  • Animals
  • Base Pair Mismatch
  • DNA Repair
  • DNA-Binding Proteins
  • Gene Expression Regulation, Neoplastic
  • Genes, p53
  • Heterozygote
  • Mice
  • Microsatellite Repeats
  • MutS Homolog 2 Protein
  • Neoplasms, Experimental
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins

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