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Chek2  -  checkpoint kinase 2

Mus musculus

Synonyms: CHK2, CHK2 checkpoint homolog, Cds1, Checkpoint kinase 2, Chk2, ...
 
 
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Disease relevance of Chek2

 

High impact information on Chek2

  • Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage [3].
  • In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA [3].
  • IR-induced stabilization of p53 in Chk2(-/- )cells was 50-70% of that in wild-type cells [4].
  • The IR-induced G(1)/S cell cycle checkpoint, but not the G(2)/M or S phase checkpoints, was impaired in embryonic fibroblasts derived from Chk2(-/-) mice [4].
  • Although Chk2(-/-) mice appeared normal, they were resistant to ionizing radiation (IR) as a result of the preservation of splenic lymphocytes [4].
 

Chemical compound and disease context of Chek2

 

Biological context of Chek2

  • The mammalian Chk2 kinase is thought to mediate ATM-dependent signaling in response to DNA damage [4].
  • We show that Chk2-/- cells, like p53-/- cells, did not undergo DNA damage-induced apoptosis, whereas Atm-/- cells behaved like normal cells in invoking an apoptotic response [1].
  • Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation [2].
  • Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes [5].
  • Among these targets, inhibition of chk2 may induce cell death for tumors whose growth depends on enhanced chk2 activity [6].
 

Anatomical context of Chek2

 

Associations of Chek2 with chemical compounds

  • Furthermore, suppression of AKT by plumbagin enhanced the activation of Chk2, resulting in increased inactive phosphorylation of Cdc25C and Cdc2 [8].
 

Regulatory relationships of Chek2

  • Likewise, Hus1 was dispensable for genotoxin-induced Chk2 phosphorylation [9].
  • However, in our present paradigms, we show that ATM functions separately from Chk2 to regulate p53 stability and neuronal death [10].
 

Other interactions of Chek2

  • These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression [11].
  • We have recently shown that Chk2 and the DNA-dependent protein kinase (DNA-PK) are both involved in DNA damage-induced apoptosis but not G(1) arrest in mouse embryo fibroblasts [12].
  • Although ectopic expression of Chk2 does not rescue the p53/p21 pathway, its expression is sufficient to allow it to phosphorylate Cdc25A, activate downstream targets, restore a G(1) arrest, and protect the cell from apoptosis [7].

References

  1. Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response. Jack, M.T., Woo, R.A., Hirao, A., Cheung, A., Mak, T.W., Lee, P.W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Hirao, A., Cheung, A., Duncan, G., Girard, P.M., Elia, A.J., Wakeham, A., Okada, H., Sarkissian, T., Wong, J.A., Sakai, T., De Stanchina, E., Bristow, R.G., Suda, T., Lowe, S.W., Jeggo, P.A., Elledge, S.J., Mak, T.W. Mol. Cell. Biol. (2002) [Pubmed]
  3. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Zhang, D., Zaugg, K., Mak, T.W., Elledge, S.J. Cell (2006) [Pubmed]
  4. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. Takai, H., Naka, K., Okada, Y., Watanabe, M., Harada, N., Saito, S., Anderson, C.W., Appella, E., Nakanishi, M., Suzuki, H., Nagashima, K., Sawa, H., Ikeda, K., Motoyama, N. EMBO J. (2002) [Pubmed]
  5. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Tan, Y., Raychaudhuri, P., Costa, R.H. Mol. Cell. Biol. (2007) [Pubmed]
  6. Oncolytic adenovirus-mediated transfer of the antisense chk2 selectively inhibits tumor growth in vitro and in vivo. Chen, G., Zhou, J., Gao, Q., Huang, X., Li, K., Zhuang, L., Huang, M., Xu, G., Wang, S., Lu, Y., Ma, D. Cancer Gene Ther. (2006) [Pubmed]
  7. Restoration of an absent G1 arrest and protection from apoptosis in embryonic stem cells after ionizing radiation. Hong, Y., Stambrook, P.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Plumbagin induces G2-M arrest and autophagy by inhibiting the AKT/mammalian target of rapamycin pathway in breast cancer cells. Kuo, P.L., Hsu, Y.L., Cho, C.Y. Mol. Cancer Ther. (2006) [Pubmed]
  9. Hus1 acts upstream of chk1 in a mammalian DNA damage response pathway. Weiss, R.S., Matsuoka, S., Elledge, S.J., Leder, P. Curr. Biol. (2002) [Pubmed]
  10. Ataxia telangiectasia-mutated protein can regulate p53 and neuronal death independent of Chk2 in response to DNA damage. Keramaris, E., Hirao, A., Slack, R.S., Mak, T.W., Park, D.S. J. Biol. Chem. (2003) [Pubmed]
  11. p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Ward, I.M., Minn, K., van Deursen, J., Chen, J. Mol. Cell. Biol. (2003) [Pubmed]
  12. DNA-dependent protein kinase and checkpoint kinase 2 synergistically activate a latent population of p53 upon DNA damage. Jack, M.T., Woo, R.A., Motoyama, N., Takai, H., Lee, P.W. J. Biol. Chem. (2004) [Pubmed]
 
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