Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice

Zheng Fu, Kevin Regan, Lizhi Zhang, Michael H. Muders, Stephen N Thibodeau, Amy French, Yanhong Wu, Scott H Kaufmann, Wilma L. Lingle, Junjie Chen, Donald James Tindall

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2714-2724
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number9
DOIs
StatePublished - Sep 1 2009

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Colonic Neoplasms
Carcinogenesis
M Phase Cell Cycle Checkpoints
Microsatellite Instability
DNA Mismatch Repair
Genomic Instability
Gene Expression Profiling
Genes
Fingers
Neoplasms
Proteins
Phosphotransferases
Down-Regulation
Chromosomes
Technology
Incidence
N-methylsuccinimide

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice. / Fu, Zheng; Regan, Kevin; Zhang, Lizhi; Muders, Michael H.; Thibodeau, Stephen N; French, Amy; Wu, Yanhong; Kaufmann, Scott H; Lingle, Wilma L.; Chen, Junjie; Tindall, Donald James.

In: Journal of Clinical Investigation, Vol. 119, No. 9, 01.09.2009, p. 2714-2724.

Research output: Contribution to journalArticle

Fu, Z, Regan, K, Zhang, L, Muders, MH, Thibodeau, SN, French, A, Wu, Y, Kaufmann, SH, Lingle, WL, Chen, J & Tindall, DJ 2009, 'Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice', Journal of Clinical Investigation, vol. 119, no. 9, pp. 2714-2724. https://doi.org/10.1172/JCI37405
Fu, Zheng ; Regan, Kevin ; Zhang, Lizhi ; Muders, Michael H. ; Thibodeau, Stephen N ; French, Amy ; Wu, Yanhong ; Kaufmann, Scott H ; Lingle, Wilma L. ; Chen, Junjie ; Tindall, Donald James. / Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 9. pp. 2714-2724.
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