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 language | English (US) |
|---|---|
| Pages (from-to) | 2714-2724 |
| Number of pages | 11 |
| Journal | Journal of Clinical Investigation |
| Volume | 119 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice
AU - Fu, Zheng
AU - Regan, Kevin
AU - Zhang, Lizhi
AU - Muders, Michael H.
AU - Thibodeau, Stephen N
AU - French, Amy
AU - Wu, Yanhong
AU - Kaufmann, Scott H
AU - Lingle, Wilma L.
AU - Chen, Junjie
AU - Tindall, Donald James
PY - 2009/9/1
Y1 - 2009/9/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=70349223855&partnerID=8YFLogxK
U2 - 10.1172/JCI37405
DO - 10.1172/JCI37405
M3 - Article
C2 - 19690386
AN - SCOPUS:70349223855
VL - 119
SP - 2714
EP - 2724
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -