The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway

Citation
Bc. Hu et al., The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway, J BIOL CHEM, 276(21), 2001, pp. 17693-17698
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
21
Year of publication
2001
Pages
17693 - 17698
Database
ISI
SICI code
0021-9258(20010525)276:21<17693:TRTKOA>2.0.ZU;2-R
Abstract
Checkpoints respond to DNA damage by arresting the cell cycle to provide ti me for facilitating repair. In mammalian cells, the G(2) checkpoint prevent s the Cdc25C phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. Both Chk1 and Chk2, the checkpoint kinases, can phosphorylate Cdc25C and inactivate its in vitro phosphatase activity. Therefore, both Chk1 and Chk2 are thought to regulate the activation of th e G(2) checkpoint. Here we report that A1-5, a transformed rat embryo fibro blast cell line, shows much more radioresistance associated with a much str onger G(2) arrest response when compared with its counterpart, B4, although A1-5 and B4 cells have a similar capacity for nonhomologous end-joining DN A repair. These phenotypes of A1-5 cells are accompanied by a higher Chk1 e xpression and a higher phosphorylation of Cdc2, On the other hand, Chk2 exp ression increases slightly following radiation; however, it has no differen ce between A1-5 and B4 cells. Caffeine or UCN-01 abolishes the extreme radi oresistance with the strong G(2) arrest and at the same time reduces the ph osphorylation of Cdc2 in A1-5 cells. In addition, Chk1 but not Chk2 antisen se oligonucleotide sensitizes A1-5 cells to radiation-induced killing and r educes the G(2) arrest of the cells. Taken together these results suggest t hat the Chk1/Cdc25C/Cdc2 pathway is the major player for the radioresistanc e with G(2) arrest in A1-5 cells.