title: Fhit modulates the DNA damage checkpoint response.
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.
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Taeko
authors.initials: T
authors.lastname: Inageta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D013272:Stomach Diseases / Q000139:chemically induced / Q000235:genetics / Q000628:therapy; D014162:Transfection; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D004128:Dimethylnitrosamine; D049452:Green Fluorescent Proteins; D009363:Neoplasm Proteins; D011494:Protein Kinases; D000099170:Bis(5'-adenosyl)triphosphatase; C549605:HUS1 protein, human; C462949:HUS1B protein, human; C014707:nitrosobenzylmethylamine; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse