Cdc25 Mitotic Inducer Targeted by Chk1 DNA Damage Checkpoint Kinase

Abstract

Arrest of the cell cycle at the G2 checkpoint, induced by DNA damage, requires inhibitory phosphorylation of the kinase Cdc2 in both fission yeast and human cells. The kinase Wee1 and the phosphatase Cdc25, which regulate Cdc2 phosphorylation, were evaluated as targets of Chk1, a kinase essential for the checkpoint. Fission yeast cdc2-3w Deltacdc25 cells, which express activated Cdc2 and lack Cdc25, were responsive to Wee1 but insensitive to Chk1 and irradiation. Expression of large amounts of Chk1 produced the same phenotype as did loss of the cdc25 gene in cdc2-3w cells. Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes. These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint.

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

“…Localization of Cdc25 is determined by the 14-3-3 protein (Conklin et al, 1995;Furnari et al, 1997;Peng et al, 1997;Dalal et al, 1999;Kumagai and Dunphy, 1999;Giles et al, 2003;Uchida et al, 2004) that binds the phosphatase and prevents its transport into the nucleus (Zeng and Piwnica-Worms, 1999;Davezac et al, 2000;Graves et al, 2001;Giles et al, 2003). The 14-3-3 family of proteins consists of small, acidic, highly conserved proteins that are present in all eukaryotic cells from yeast to mammals (Hermeking and Benzinger, 2006).…”

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

“…In S. pombe several mutants have been described that are unable to arrest the cell cycle in response to DNA damage at the G2 checkpoint (Weinert and Hartwell, 1990;AlKhodairy et al, 1994;Ford et al, 1994). One of these genes, chk1, encodes a protein kinase that appears to function downstream of all other checkpoint genes to elicit a cell cycle arrest via cdc25 and wee1 to maintain tyrosine phosphorylation of p34 cdc2 (O'Connell et al, 1997;Rhind et al, 1997;Furnari et al, 1997;Sanchez et al, 1997). Irradiation of cells leads to phosphorylation of chk1 itself, and this response requires all of the upstream checkpoint components, including rad3 (Walworth and Bernards, 1996).…”

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…The checkpoint kinase regulates the activation of downstream Cdc25 phosphatases especially Cdc25A and Cdc25B which remove phosphates from inhibitory tyrosine and threonine residues of cyclin-dependant kinases (CDKs) are essential for cell cycle progression (Furnari et al, 1997;Sanchez et al, 1997). Afterward, the activated cyclin-CDK complex finally contributes cell cycle to further progress (Xiao et al, 2003) (Fig.…”