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J. Biol. Chem., Vol. 276, Issue 21, 17693-17698, May 25, 2001
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From the Department of Radiation Oncology, Kimmel Cancer Center of
Jefferson Medical College, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
Checkpoints respond to DNA damage by arresting
the cell cycle to provide time for facilitating repair. In mammalian
cells, the G2 checkpoint prevents 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 the G2 checkpoint.
Here we report that A1-5, a transformed rat embryo fibroblast cell
line, shows much more radioresistance associated with a much stronger
G2 arrest response when compared with its counterpart, B4,
although A1-5 and B4 cells have a similar capacity for nonhomologous
end-joining DNA repair. These phenotypes of A1-5 cells are accompanied
by a higher Chk1 expression and a higher phosphorylation of Cdc2. On
the other hand, Chk2 expression increases slightly following radiation;
however, it has no difference between A1-5 and B4 cells. Caffeine or
UCN-01 abolishes the extreme radioresistance with the strong
G2 arrest and at the same time reduces the phosphorylation of Cdc2 in A1-5 cells. In addition, Chk1 but not Chk2 antisense oligonucleotide sensitizes A1-5 cells to radiation-induced killing and
reduces the G2 arrest of the cells. Taken together these
results suggest that the Chk1/Cdc25C/Cdc2 pathway is the major player for the radioresistance with G2 arrest in A1-5 cells.
The Radioresistance to Killing of A1-5 Cells Derives from
Activation of the Chk1 Pathway*
*
This work was supported by National Institutes of Health
Grants CA76203, T32-CA09137, and P30-CA56036 and by NASA Grant
NAG-1023. Support was also provided by a grant from RTOG.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Thomas Jefferson
University, Thompson Bldg., B13, 11th and Walnut St., Philadelphia, PA
19107. Tel.: 215-955-2045; Fax: 215-955-2052; E-mail:
ya.wang@mail.tju.edu.
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