Abstract
Fragile Histidine Triad (Fhit) gene deletion, methylation, and reduced Fhit protein expression occur in about 70% of human epithelial tumors and, in some cancers, are clearly associated with tumor progression. Specific Fhit signal pathways have not been identified, although it has been shown that Fhit overexpression leads to apoptosis in many cancer cell lines. We report in this study that Fhit-/- cells derived from gene knockout mice show much stronger S and G2 checkpoint responses than their wild type counterparts. The strong checkpoint responses are regulated by the ATR/CHK1 pathway, which contributes to the radioresistance of Fhit-/- cells. These results indicate an association of Fhit gene inactivation with increased survival after DNA damage, which is related to the over-active checkpoints regulated by the ATR/CHK1 pathway. These results also suggest the potential effects of Fhit-dependent DNA damage response on tumor progression.
2004 Wiley-Liss, Inc.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Acid Anhydride Hydrolases / genetics
-
Acid Anhydride Hydrolases / physiology*
-
Animals
-
Ataxia Telangiectasia Mutated Proteins
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism*
-
Cell Death
-
Cell Line
-
Checkpoint Kinase 1
-
Kidney / cytology
-
Kidney / drug effects
-
Kidney / metabolism*
-
Kidney / radiation effects*
-
Mice
-
Mice, Knockout
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / physiology*
-
Protein Kinases / genetics
-
Protein Kinases / metabolism*
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
RNA, Small Interfering / pharmacology
Substances
-
Cell Cycle Proteins
-
Neoplasm Proteins
-
RNA, Small Interfering
-
fragile histidine triad protein
-
Protein Kinases
-
Atr protein, mouse
-
Ataxia Telangiectasia Mutated Proteins
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
Chek1 protein, mouse
-
Protein Serine-Threonine Kinases
-
Acid Anhydride Hydrolases