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Advances in Brief |
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [E. C. B., D. F. L., L. M. K., J. N. S.], and Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710 [R. T. A.]
The investigational anticancer agent 7-hydroxystaurosporine (UCN-01)
abrogates the G2 checkpoint in tumor cells and sensitizes
them to the lethal effects of genotoxic anticancer agents. On the basis
of the role of the Cdc25C phosphatase in maintenance of this
damage-inducible checkpoint, we hypothesized that UCN-01 inhibits a
component of the signal transduction pathway that modulates Cdc25C
phosphorylation. Of the three kinases known to phosphorylate Cdc25C on
Ser216, both checkpoint kinase 1 (hChk1) and
Cdc25C-associated protein kinase 1 (cTAK1) were potently
inhibited by UCN-01 with IC50s of 11 and 27 nM,
respectively. Treatment of K562 erythroblastoid leukemia cells with
similar drug concentrations resulted in decreased levels of
Ser216 phosphorylation of Cdc25C and complete disruption of
the
-radiation-induced G2 checkpoint. In contrast to
hChk1, the hChk2 kinase was 100-fold more resistant to inhibition by
UCN-01 (IC50, 1040 nM). These results suggest
that disruption of the DNA damage-induced G2 checkpoint by
UCN-01 is mediated through the inhibition of the Cdc25C kinases, hChk1
and cTAK1, and that hChk2 activity is not sufficient to enforce the
G2 checkpoint in cells treated with a pharmacological
inhibitor of hChk1.
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J. R. A. Hutchins, D. Dikovskaya, and P. R. Clarke Regulation of Cdc2/Cyclin B Activation in Xenopus Egg Extracts via Inhibitory Phosphorylation of Cdc25C Phosphatase by Ca2+/Calmodium-dependent Kinase II Mol. Biol. Cell, October 1, 2003; 14(10): 4003 - 4014. [Abstract] [Full Text] [PDF] |
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T. Yamauchi, M. J. Keating, and W. Plunkett UCN-01 (7-Hydroxystaurosporine) Inhibits DNA Repair and Increases Cytotoxicity in Normal Lymphocytes and Chronic Lymphocytic Leukemia Lymphocytes Mol. Cancer Ther., February 1, 2002; 1(4): 287 - 294. [Abstract] [Full Text] [PDF] |
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E. A. Sausville Combining Cytotoxics and 17-Allylamino, 17-Demethoxygeldanamycin: Sequence and Tumor Biology Matters : Commentary re: P. Munster et al., Modulation of Hsp90 Function by Ansamycins Sensitizes Breast Cancer Cells to Chemotherapy-induced Apoptosis in an RB- and Schedule-dependent Manner. Clin. Cancer Res., 7: 2228-2236, 2001. Clin. Cancer Res., August 1, 2001; 7(8): 2155 - 2158. [Full Text] [PDF] |
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M. A. Shah and G. K. Schwartz Cell Cycle-mediated Drug Resistance: An Emerging Concept in Cancer Therapy Clin. Cancer Res., August 1, 2001; 7(8): 2168 - 2181. [Abstract] [Full Text] [PDF] |
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H. Zhao and H. Piwnica-Worms ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1 Mol. Cell. Biol., July 1, 2001; 21(13): 4129 - 4139. [Abstract] [Full Text] [PDF] |
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E. A. Sausville, S. G. Arbuck, R. Messmann, D. Headlee, K. S. Bauer, R. M. Lush, A. Murgo, W. D. Figg, T. Lahusen, S. Jaken, et al. Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms J. Clin. Oncol., April 15, 2001; 19(8): 2319 - 2333. [Abstract] [Full Text] [PDF] |
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H. Miyata, Y. Doki, H. Yamamoto, K. Kishi, H. Takemoto, Y. Fujiwara, T. Yasuda, M. Yano, M. Inoue, H. Shiozaki, et al. Overexpression of CDC25B Overrides Radiation-induced G2-M Arrest and Results in Increased Apoptosis in Esophageal Cancer Cells Cancer Res., April 1, 2001; 61(7): 3188 - 3193. [Abstract] [Full Text] |
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Y. Hirose, M. S. Berger, and R. O. Pieper p53 Effects Both the Duration of G2/M Arrest and the Fate of Temozolomide-treated Human Glioblastoma Cells Cancer Res., March 1, 2001; 61(5): 1957 - 1963. [Abstract] [Full Text] |
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V. Gottifredi, O. Karni-Schmidt, S.-Y. Shieh, and C. Prives p53 Down-Regulates CHK1 through p21 and the Retinoblastoma Protein Mol. Cell. Biol., February 15, 2001; 21(4): 1066 - 1076. [Abstract] [Full Text] |
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Z. Shi, A. Azuma, D. Sampath, Y.-X. Li, P. Huang, and W. Plunkett S-Phase Arrest by Nucleoside Analogues and Abrogation of Survival without Cell Cycle Progression by 7-Hydroxystaurosporine Cancer Res., February 1, 2001; 61(3): 1065 - 1072. [Abstract] [Full Text] |
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N Rhind and P Russell Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways J. Cell Sci., January 11, 2000; 113(22): 3889 - 3896. [Abstract] [PDF] |
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B. Hu, X.-Y. Zhou, X. Wang, Z.-C. Zeng, G. Iliakis, and Y. Wang The Radioresistance to Killing of A1-5 Cells Derives from Activation of the Chk1 Pathway J. Biol. Chem., May 18, 2001; 276(21): 17693 - 17698. [Abstract] [Full Text] [PDF] |
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X. Wu, S. R. Webster, and J. Chen Characterization of Tumor-associated Chk2 Mutations J. Biol. Chem., January 19, 2001; 276(4): 2971 - 2974. [Abstract] [Full Text] [PDF] |
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D. Curman, B. Cinel, D. E. Williams, N. Rundle, W. D. Block, A. A. Goodarzi, J. R. Hutchins, P. R. Clarke, B.-B. Zhou, S. P. Lees-Miller, et al. Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine J. Biol. Chem., May 18, 2001; 276(21): 17914 - 17919. [Abstract] [Full Text] [PDF] |
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W. A. Cliby, K. A. Lewis, K. K. Lilly, and S. H. Kaufmann S Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function J. Biol. Chem., January 4, 2002; 277(2): 1599 - 1606. [Abstract] [Full Text] [PDF] |
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P. B. Deming, C. A. Cistulli, H. Zhao, P. R. Graves, H. Piwnica-Worms, R. S. Paules, C. S. Downes, and W. K. Kaufmann The human decatenation checkpoint PNAS, October 9, 2001; 98(21): 12044 - 12049. [Abstract] [Full Text] [PDF] |
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