Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice

J Clin Invest. 2009 Sep;119(9):2714-24. doi: 10.1172/JCI37405. Epub 2009 Aug 17.

Abstract

Genetic instability, which leads to an accumulation of various genetic abnormalities, has been considered an essential component of the human neoplasic transformation process. However, the molecular basis of genomic instability during tumorigenesis remains incompletely understood. Growing evidence indicates that checkpoint with forkhead and ring finger domains (CHFR), a recently identified mitotic checkpoint protein, plays an important role in maintaining chromosome integrity and functions as a tumor suppressor. In this study, we used high-throughput technology to conduct gene expression profiling of human colon cancers and found that loss of CHFR expression frequently occurred in colon cancers with high microsatellite instability (MSI-H). Downregulation of CHFR expression was closely associated with overexpression of Aurora A, an important mitotic kinase. Mice with deficiencies in both Chfr and Mlh1 (the gene that encodes the DNA mismatch-repair protein Mlh1) displayed dramatically higher incidence of spontaneous tumors relative to mice deficient for only one of these genes. These results suggest that defects in both Chfr and Mlh1 synergistically increase predisposition to tumorigenesis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Base Sequence
  • Cell Cycle Proteins / genetics
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • DNA Primers / genetics
  • Down-Regulation
  • Female
  • Genes, cdc*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsatellite Instability
  • Middle Aged
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics
  • Neoplasms, Experimental / etiology
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / metabolism*
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA Primers
  • Mlh1 protein, mouse
  • Neoplasm Proteins
  • Nuclear Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • CHFR protein, human
  • Ubiquitin-Protein Ligases
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • MutL Protein Homolog 1