Abstract
In preneoplastic lesions, the DNA damage checkpoint is induced and loss of heterozygosity at the FRA3B/FHIT common chromosome fragile region precedes or is coincident with activation of the checkpoint response in these early stages. Introduction of exogenous Fhit into cells in vitro led to modulation of expression of checkpoint proteins Hus1 and Chk1 at mid-S checkpoint, a modulation that led to induction of apoptosis in esophageal cancer cells but not in noncancerous primary cultures. Mutation of the conserved Fhit tyrosine 114 resulted in failure of this function, confirming the importance of this residue. The results suggest that the DNA damage-susceptible FRA3B/FHIT chromosome fragile region, paradoxically, encodes a protein that is necessary for protecting cells from accumulation of DNA damage through its role in modulation of checkpoint proteins, and inactivation of Fhit contributes to accumulation of abnormal checkpoint phenotypes in cancer development.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acid Anhydride Hydrolases / genetics
-
Acid Anhydride Hydrolases / metabolism
-
Acid Anhydride Hydrolases / physiology*
-
Animals
-
Apoptosis / genetics
-
Apoptosis / physiology*
-
Cell Cycle / genetics
-
Cell Cycle / physiology
-
Cell Cycle Proteins / metabolism*
-
Cell Line
-
Cell Line, Tumor
-
Checkpoint Kinase 1
-
DNA Damage*
-
Dimethylnitrosamine / analogs & derivatives
-
Esophageal Neoplasms / genetics
-
Esophageal Neoplasms / metabolism
-
Esophageal Neoplasms / pathology
-
Genetic Therapy
-
Genetic Vectors / genetics
-
Green Fluorescent Proteins / genetics
-
Green Fluorescent Proteins / metabolism
-
Humans
-
Immunoblotting
-
Immunohistochemistry
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Microscopy, Fluorescence
-
Mutation / genetics
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Neoplasm Proteins / physiology*
-
Protein Kinases / metabolism
-
Stomach Diseases / chemically induced
-
Stomach Diseases / genetics
-
Stomach Diseases / therapy
-
Transfection
Substances
-
Cell Cycle Proteins
-
HUS1 protein, human
-
HUS1B protein, human
-
Neoplasm Proteins
-
fragile histidine triad protein
-
Green Fluorescent Proteins
-
nitrosobenzylmethylamine
-
Protein Kinases
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
Chek1 protein, mouse
-
Acid Anhydride Hydrolases
-
Dimethylnitrosamine