Cell Cycle / Checkpoint Control

Chk1 kinase acts downstream of ATM/ATR kinase and plays an important role in DNA damage checkpoint control, embryonic development, and tumor suppression (1). Activation of Chk1 involves phosphorylation at Ser317 and Ser345 and occurs in response to blocked DNA replication and certain forms of genotoxic stress (2). While phosphorylation at Ser345 serves to localize Chk1 to the nucleus following checkpoint activation (3), phosphorylation at Ser317 along with site-specific phosphorylation of PTEN allows for reentry into the cell cycle following stalled DNA replication (4). Chk1 exerts its checkpoint mechanism on the cell cycle, in part, by regulating the cdc25 family of phosphatases. Chk1 phosphorylation of cdc25A targets it for proteolysis and inhibits its activity through 14-3-3 binding (5). Activated Chk1 can inactivate cdc25C via phosphorylation at Ser216, blocking the activation of cdc2 and transition into mitosis (6). Centrosomal Chk1 has been shown to phosphorylate cdc25B and inhibit its activation of CDK1-cyclin B1, thereby abrogating mitotic spindle formation and chromatin condensation (7). Furthermore, Chk1 plays a role in spindle checkpoint function through regulation of Aurora B and BubR1 (8). Chk1 has emerged as a drug target for cancer therapy as its inhibition leads to cell death in many cancer cell lines (9).

1. Liu, Q. et al. (2000) Genes Dev 14, 1448-59.
2. Zhao, H. and Piwnica-Worms, H. (2001) Mol Cell Biol 21, 4129-39.
3. Jiang, K. et al. (2003) J Biol Chem 278, 25207-17.
4. Martin, S.A. and Ouchi, T. (2008) Mol Cancer Ther 7, 2509-16.
5. Chen, M.S. et al. (2003) Mol Cell Biol 23, 7488-97.
6. Zeng, Y. et al. (1998) Nature 395, 507-10.
7. Löffler, H. et al. (2006) Cell Cycle 5, 2543-7.
8. Zachos, G. et al. (2007) Dev Cell 12, 247-60.
9. Garber, K. (2005) J Natl Cancer Inst 97, 1026-8.

• Cliby, W. A. et al. (2002) S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J. Biol. Chem. 277 (2), 1599-1606. Applications: Western Blotting
• Castedo, M. et al. (2004) The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Oncogene 23, 4353-4361. Applications: Western Blotting
• d'Adda di Fagagna, F. et al. (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194-198. Applications: Western Blotting
• Fang, Y. et al. (2004) ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background. EMBO J. 23, 3164-3174. Applications: Western Blotting
• Shibata, Y. and Nakamura, T. (2002) Defective flap endonuclease 1 activity in mammalian cells is associated with impaired DNA repair and prolonged S phase delay. J. Biol. Chem. 277, 746-754. Applications: Western Blot
• Deming , P. B. et al. (2001) The human decatenation checkpoint. Proc. Natl. Acad. Sci. USA 98, 12044-12049. Applications: Western Blot
• Nam, E.A. et al. (2011) J Biol Chem 286, 28707-14. Applications: Western Blotting

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Phospho-Chk1 (Ser345) Antibody

©1999-2012 Cell Signaling Technology, Inc.

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