Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract??? Cdc25 phosphatases activate cyclin-dependent kinases (Cdks) and thereby promote cell cycle progression. In vertebrates, Chk1 and Chk2 phosphorylate Cdc25A at multiple N-terminal sites and target it for rapid degradation in response to genotoxic stress. Here we show that Chk1, but not Chk2, phosphorylates Xenopus Cdc25A at a novel C-terminal site (Thr504) and inhibits it from C-terminally interacting with various Cdk-cyclin complexes, including Cdk1-cyclin A, Cdk1-cyclin B, and Cdk2-cyclin E. Strikingly, this inhibition, rather than degradation itself, of Cdc25A is essential for the Chk1-induced cell cycle arrest and the DNA replication checkpoint in early embryos. 14-3-3 proteins bind to Chk1-phosphorylated Thr504, but this binding is not required for the inhibitory effect of Thr504 phosphorylation. A C-terminal site presumably equivalent to Thr504 exists in all known Cdc25 family members from yeast to humans, and its phosphorylation by Chk1 (but not Chk2) can also inhibit all examined Cdc25 family members from C-terminally interacting with their Cdk-cyclin substrates. Thus, Chk1 but not Chk2 seems to inhibit virtually all Cdc25 phosphatases by a novel common mechanism.
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed Barlow,
Atm-deficient mice: a paradigm of ataxia telangiectasia.
1996,
Pubmed Bartek,
Chk1 and Chk2 kinases in checkpoint control and cancer.
2003,
Pubmed Blasina,
A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.
1999,
Pubmed Bulavin,
Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase.
2001,
Pubmed Busino,
Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.
2003,
Pubmed Chen,
Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding.
2003,
Pubmed Donzelli,
Regulating mammalian checkpoints through Cdc25 inactivation.
2003,
Pubmed Edgar,
Genetic control of cell division patterns in the Drosophila embryo.
1989,
Pubmed Falck,
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.
2001,
Pubmed Furnari,
Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1.
1999,
Pubmed Goloudina,
Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint.
2003,
Pubmed Guo,
Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase Hartwell,
Checkpoints: controls that ensure the order of cell cycle events.
1989,
Pubmed Hoffmann,
Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition.
1994,
Pubmed Jinno,
Cdc25A is a novel phosphatase functioning early in the cell cycle.
1994,
Pubmed Katsuragi,
Regulation of Chk1 kinase by autoinhibition and ATR-mediated phosphorylation.
2004,
Pubmed
,
Xenbase Kumagai,
Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25.
1999,
Pubmed
,
Xenbase Kumagai,
The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
1998,
Pubmed
,
Xenbase Lammer,
The cdc25B phosphatase is essential for the G2/M phase transition in human cells.
1998,
Pubmed Lee,
Positive regulation of Wee1 by Chk1 and 14-3-3 proteins.
2001,
Pubmed
,
Xenbase Liu,
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.
2000,
Pubmed Lopez-Girona,
Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein.
1999,
Pubmed Mailand,
Rapid destruction of human Cdc25A in response to DNA damage.
2000,
Pubmed Mailand,
Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability.
2002,
Pubmed Matsuoka,
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
1998,
Pubmed Molinari,
Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis.
2000,
Pubmed Nurse,
Checkpoint pathways come of age.
1997,
Pubmed Oe,
Cytoplasmic occurrence of the Chk1/Cdc25 pathway and regulation of Chk1 in Xenopus oocytes.
2001,
Pubmed
,
Xenbase Okamoto,
The existence of two distinct Wee1 isoforms in Xenopus: implications for the developmental regulation of the cell cycle.
2002,
Pubmed
,
Xenbase Peng,
Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
1997,
Pubmed Rhind,
Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways.
2000,
Pubmed Saha,
p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases.
1997,
Pubmed
,
Xenbase Sanchez,
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
1997,
Pubmed Sarkaria,
Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
1999,
Pubmed Shiloh,
ATM and ATR: networking cellular responses to DNA damage.
2001,
Pubmed Shimuta,
Chk1 is activated transiently and targets Cdc25A for degradation at the Xenopus midblastula transition.
2002,
Pubmed
,
Xenbase Sibon,
DNA-replication checkpoint control at the Drosophila midblastula transition.
1997,
Pubmed Sørensen,
Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
2003,
Pubmed Takizawa,
Control of mitosis by changes in the subcellular location of cyclin-B1-Cdk1 and Cdc25C.
2000,
Pubmed
,
Xenbase Walworth,
Cell-cycle checkpoint kinases: checking in on the cell cycle.
2000,
Pubmed Wilborn,
The C-terminal tail of the dual-specificity Cdc25B phosphatase mediates modular substrate recognition.
2001,
Pubmed Xu,
Chk2 activation and phosphorylation-dependent oligomerization.
2002,
Pubmed Xu,
Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25.
1996,
Pubmed Zhao,
Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.
2002,
Pubmed Zhou,
The DNA damage response: putting checkpoints in perspective.
2000,
Pubmed
