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Science 5 September 1997:
Vol. 277. no. 5331, pp. 1497 - 1501
DOI: 10.1126/science.277.5331.1497
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Reports

Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25

Yolanda Sanchez, Calvin Wong, Richard S. Thoma, Ron Richman, Zhiqi Wu, Helen Piwnica-Worms, Stephen J. Elledge *

In response to DNA damage, mammalian cells prevent cell cycle progression through the control of critical cell cycle regulators. A human gene was identified that encodes the protein Chk1, a homolog of the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein was modified in response to DNA damage. In vitro Chk1 bound to and phosphorylated the dual-specificity protein phosphatases Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by dephosphorylating cyclin-dependent kinases. Chk1 phosphorylates Cdc25C on serine-216. As shown in an accompanying paper by Peng et al. in this issue, serine-216 phosphorylation creates a binding site for 14-3-3 protein and inhibits function of the phosphatase. These results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2-cyclin B complex and mitotic entry.

Y. Sanchez, C. Wong, S. J. Elledge, Verna and Marrs McLean Department of Biochemistry, Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
R. S. Thoma, Z. Wu, H. Piwnica-Worms, Department of Cell Biology and Physiology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
R. Richman, Department of Cell Biology, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: selledge{at}bcm.tmc.edu

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J. Biol. Chem. 279, 31251-31258
   Abstract »    Full Text »    PDF »
Binding of 14-3-3{beta} but not 14-3-3{sigma} controls the cytoplasmic localization of CDC25B: binding site preferences of 14-3-3 subtypes and the subcellular localization of CDC25B.
S. Uchida, A. Kuma, M. Ohtsubo, M. Shimura, M. Hirata, H. Nakagama, T. Matsunaga, Y. Ishizaka, and K. Yamashita (2004)
J. Cell Sci. 117, 3011-3020
   Abstract »    Full Text »    PDF »
Sulforaphane-induced G2/M Phase Cell Cycle Arrest Involves Checkpoint Kinase 2-mediated Phosphorylation of Cell Division Cycle 25C.
S. V. Singh, A. Herman-Antosiewicz, A. V. Singh, K. L. Lew, S. K. Srivastava, R. Kamath, K. D. Brown, L. Zhang, and R. Baskaran (2004)
J. Biol. Chem. 279, 25813-25822
   Abstract »    Full Text »    PDF »
Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.
S.-Y. Lin, K. Li, G. S. Stewart, and S. J. Elledge (2004)
PNAS 101, 6484-6489
   Abstract »    Full Text »    PDF »
Unlocking the code of 14-3-3.
M. K. Dougherty and D. K. Morrison (2004)
J. Cell Sci. 117, 1875-1884
   Abstract »    Full Text »    PDF »
G2 checkpoint abrogators as anticancer drugs.
T. Kawabe (2004)
Mol. Cancer Ther. 3, 513-519
   Abstract »    Full Text »    PDF »
Regulation of Chk1 Kinase by Autoinhibition and ATR-mediated Phosphorylation.
Y. Katsuragi and N. Sagata (2004)
Mol. Biol. Cell 15, 1680-1689
   Abstract »    Full Text »    PDF »
Differential Mode of Regulation of the Checkpoint Kinases CHK1 and CHK2 by Their Regulatory Domains.
C.-P. Ng, H. C. Lee, C. W. Ho, T. Arooz, W. Y. Siu, A. Lau, and R. Y. C. Poon (2004)
J. Biol. Chem. 279, 8808-8819
   Abstract »    Full Text »    PDF »
Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease.
M. Takagi, R. Tsuchida, K. Oguchi, T. Shigeta, S. Nakada, K. Shimizu, M. Ohki, D. Delia, L. Chessa, Y. Taya, et al. (2004)
Blood 103, 283-290
   Abstract »    Full Text »    PDF »
Wee1-dependent mechanisms required for coordination of cell growth and cell division.
D. R. Kellogg (2003)
J. Cell Sci. 116, 4883-4890
   Abstract »    Full Text »    PDF »
SCF{beta}-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase.
J. Jin, T. Shirogane, L. Xu, G. Nalepa, J. Qin, S. J. Elledge, and J. W. Harper (2003)
Genes & Dev. 17, 3062-3074
   Abstract »    Full Text »    PDF »
p73{alpha} Regulation by Chk1 in Response to DNA Damage.
S. Gonzalez, C. Prives, and C. Cordon-Cardo (2003)
Mol. Cell. Biol. 23, 8161-8171
   Abstract »    Full Text »    PDF »
The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents.
Y. Hirose, M. Katayama, D. Stokoe, D. A. Haas-Kogan, M. S. Berger, and R. O. Pieper (2003)
Mol. Cell. Biol. 23, 8306-8315
   Abstract »    Full Text »    PDF »
DNA Damage-induced G2/M Checkpoint in SV40 Large T Antigen-immortalized Embryonic Fibroblast Cells Requires SHP-2 Tyrosine Phosphatase.
L. Yuan, W.-M. Yu, and C.-K. Qu (2003)
J. Biol. Chem. 278, 42812-42820
   Abstract »    Full Text »    PDF »
Regulation of Cdc2/Cyclin B Activation in Xenopus Egg Extracts via Inhibitory Phosphorylation of Cdc25C Phosphatase by Ca2+/Calmodium-dependent Kinase II.
J. R. A. Hutchins, D. Dikovskaya, and P. R. Clarke (2003)
Mol. Biol. Cell 14, 4003-4014
   Abstract »    Full Text »    PDF »
The BCSC-1 locus at chromosome 11q23-q24 is a candidate tumor suppressor gene.
E. S. Martin, R. Cesari, F. Pentimalli, K. Yoder, R. Fishel, A. L. Himelstein, S. E. Martin, A. K. Godwin, M. Negrini, and C. M. Croce (2003)
PNAS 100, 11517-11522
   Abstract »    Full Text »    PDF »
Caffeine Inhibits Checkpoint Responses without Inhibiting the Ataxia-Telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein Kinases.
D. Cortez (2003)
J. Biol. Chem. 278, 37139-37145
   Abstract »    Full Text »    PDF »
Forced expression of antisense 14-3-3{beta} RNA suppresses tumor cell growth in vitro and in vivo.
A. Sugiyama, Y. Miyagi, Y. Komiya, N. Kurabe, C. Kitanaka, N. Kato, Y. Nagashima, Y. Kuchino, and F. Tashiro (2003)
Carcinogenesis 24, 1549-1559
   Abstract »    Full Text »    PDF »
XRad17 Is Required for the Activation of XChk1 But Not XCds1 during Checkpoint Signaling in Xenopus.
R. E. Jones, J. R. Chapman, C. Puligilla, J. M. Murray, A. M. Car, C. C. Ford, and H. D. Lindsay (2003)
Mol. Biol. Cell 14, 3898-3910
   Abstract »    Full Text »    PDF »
Regulation of Cdc25A Half-life in Interphase by Cyclin-dependent Kinase 2 Activity.
A. P. Ducruet and J. S. Lazo (2003)
J. Biol. Chem. 278, 31838-31842
   Abstract »    Full Text »    PDF »


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