Involvement of the Fhit gene in the ionizing radiation-activated ATR/CHK1 pathway.
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.
Hu
Baocheng
B
Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Han
Shuang-Yin
SY
Wang
Xiang
X
Ottey
Michelle
M
Potoczek
Magdalena B
MB
Dicker
Adam
A
Huebner
Kay
K
Wang
Ya
Y
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D009363:Neoplasm Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099170:Bis(5'-adenosyl)triphosphatase; C576897:Atr protein, mouse; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse