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CHEK1  -  checkpoint kinase 1

Homo sapiens

Synonyms: CHK1, CHK1 checkpoint homolog, Cell cycle checkpoint kinase, Checkpoint kinase-1, Serine/threonine-protein kinase Chk1
 
 
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Disease relevance of CHEK1

  • UCN-01 (7-hydroxystaurosporine), a CHEK1 inhibitor that abrogates the G(2) block, has been reported to enhance radiation toxicity in human lymphoma and colon cancer cell lines [1].
  • Chk1 expression was markedly reduced in primary fibroblasts and U2OS osteogenic sarcoma cells by treatment with small molecule Cdk inhibitors or induction of a dominant-negative mutant of Cdk2 [2].
  • Furthermore, these results suggest that the inhibition of the ATR-CHK1 DNA damage-response pathway might be involved in the tumorigenesis of gastric cancer with microsatellite instability [3].
  • To our knowledge, this is the first CHK1/CHK2 mutation screening in human melanoma [4].
  • Moreover, selective targeting of plk1 or chk1 in tumor xenografts of mice by oncolytic adenovirus mutants demonstrated potent anti-tumoral efficacy in the presence of low dose cisplatin [5].
  • Further research is warranted to validate the use of Chk1 inhibitors in triple-negative breast carcinomas for which treatment strategies are limited at present [6].
 

High impact information on CHEK1

  • Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest [7].
  • In addition, cells lacking MDC1 also fail to activate the intra-S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing radiation, which was associated with an inability to regulate Chk1 properly [8].
  • Fission yeast cdc2-3w Deltacdc25 cells, which express activated Cdc2 and lack Cdc25, were responsive to Wee1 but insensitive to Chk1 and irradiation [9].
  • Chk1, a fission yeast kinase involved in the DNA damage checkpoint response, phosphorylated Cdc25C in vitro on serine-216 [10].
  • Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes [9].
 

Chemical compound and disease context of CHEK1

 

Biological context of CHEK1

 

Anatomical context of CHEK1

 

Associations of CHEK1 with chemical compounds

 

Physical interactions of CHEK1

  • Additionally, microcephalin interacts with Chk1 [29].
  • Dbf4 interacted weakly with Chk1 in vivo but was recognized as a substrate for Chk1-dependent phosphorylation in vitro [30].
  • In this study, we show that Chk1 interacts with Hsp90, a molecular chaperone that participates in the folding, assembly, maturation, and stabilization of specific proteins known as clients [31].
  • Several E2F binding sites were detected in the genomic sequence and E2F1 induced Chk1 promoter activity in co-transfection experiments [32].
  • Direct requirement for Xmus101 in ATR-mediated phosphorylation of Claspin bound Chk1 during checkpoint signaling [33].
 

Enzymatic interactions of CHEK1

  • Additional inducible amino- and carboxy-terminal sites in p53 are also phosphorylated by hCHK1, indicating that this is an unusually versatile protein kinase [34].
  • Consistently, the RNAi-mediated ablation of Claspin selectively abrogated ATR's ability to phosphorylate Chk1 but not other ATR targets [19].
  • The basic mechanism of this assay is to observe the phosphorylated levels of a fragment of CDC25C containing the site that can be phosphorylated by CHK1 in vitro [35].
  • Chk1 phosphorylates Tlk1 on serine 695 (S695) in vitro, and this UCN-01- and caffeine-sensitive site is phosphorylated in vivo in response to DNA damage [36].
  • We have shown recently that DNA damage effector kinase Chk1 is phosphorylated in vitro by protein kinase B/Akt (PKB/Akt) on serine 280 [37].
 

Regulatory relationships of CHEK1

  • RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage [29].
  • Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1 [20].
  • In this study we found that in ovarian cancer cells, CHK2 kinase is activated by irofulven while CHK1 kinase is not activated even when treated at higher concentrations of the drug [38].
  • Using small interfering RNA technology, we have shown that down-regulation of Claspin expression inhibits Chk1 activation in response to replication stress [39].
  • Finally, we found that CHK1 was upregulated in primary hepatocellular carcinoma (HCC), albeit as an inactive form [40].
 

Other interactions of CHEK1

  • We confirmed that recombinant hCHK1, but not a kinase-defective version of hCHK1, can phosphorylate p53 in vitro at S20 [34].
  • Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair [17].
  • Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay [41].
  • Time course experiments showed that the bulk of ATM activation followed Chk1 down-regulation [2].
  • Mcph1 inhibition also decreases both endogenous and heterologous Chk1 transcripts and protein [42].
  • These results suggest that Chk1 is activated by caspase-mediated cleavage during apoptosis and might be implicated in enhancing apoptotic reactions rather than attenuating the ATR-Chk1 pathway [43].
 

Analytical, diagnostic and therapeutic context of CHEK1

References

  1. 7-Hydroxystaurosporine (UCN-01) preferentially sensitizes cells with a disrupted TP53 to gamma radiation in lung cancer cell lines. Xiao, H.H., Makeyev, Y., Butler, J., Vikram, B., Franklin, W.A. Radiat. Res. (2002) [Pubmed]
  2. Cdk inhibition in human cells compromises chk1 function and activates a DNA damage response. Maude, S.L., Enders, G.H. Cancer Res. (2005) [Pubmed]
  3. Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. Menoyo, A., Alazzouzi, H., Espín, E., Armengol, M., Yamamoto, H., Schwartz, S. Cancer Res. (2001) [Pubmed]
  4. Mutational analysis of Chk1, Chk2, Apaf1 and Rb1 in human malignant melanoma cell lines. Papp, T., Niemetz, A., Dosdahl, N., Kumar, K., Schiffmann, D. Oncol. Rep. (2007) [Pubmed]
  5. Influence of chk1 and plk1 silencing on radiation- or cisplatin-induced cytotoxicity in human malignant cells. Gao, Q., Huang, X., Tang, D., Cao, Y., Chen, G., Lu, Y., Zhuang, L., Wang, S., Xu, G., Zhou, J., Ma, D. Apoptosis (2006) [Pubmed]
  6. The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor /progesterone receptor /HER-2 breast carcinomas. Verlinden, L., Vanden Bempt, I., Eelen, G., Drijkoningen, M., Verlinden, I., Marchal, K., De Wolf-Peeters, C., Christiaens, M.R., Michiels, L., Bouillon, R., Verstuyf, A. Cancer Res. (2007) [Pubmed]
  7. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Yarden, R.I., Pardo-Reoyo, S., Sgagias, M., Cowan, K.H., Brody, L.C. Nat. Genet. (2002) [Pubmed]
  8. MDC1 is a mediator of the mammalian DNA damage checkpoint. Stewart, G.S., Wang, B., Bignell, C.R., Taylor, A.M., Elledge, S.J. Nature (2003) [Pubmed]
  9. Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Furnari, B., Rhind, N., Russell, P. Science (1997) [Pubmed]
  10. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Peng, C.Y., Graves, P.R., Thoma, R.S., Wu, Z., Shaw, A.S., Piwnica-Worms, H. Science (1997) [Pubmed]
  11. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Mesa, R.A., Loegering, D., Powell, H.L., Flatten, K., Arlander, S.J., Dai, N.T., Heldebrant, M.P., Vroman, B.T., Smith, B.D., Karp, J.E., Eyck, C.J., Erlichman, C., Kaufmann, S.H., Karnitz, L.M. Blood (2005) [Pubmed]
  12. Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Hirose, Y., Berger, M.S., Pieper, R.O. Cancer Res. (2001) [Pubmed]
  13. Geldanamycin-induced degradation of Chk1 is mediated by proteasome. Nomura, M., Nomura, N., Yamashita, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  14. A novel mechanism of checkpoint abrogation conferred by Chk1 downregulation. Xiao, Z., Xue, J., Sowin, T.J., Rosenberg, S.H., Zhang, H. Oncogene (2005) [Pubmed]
  15. Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells. Laezza, C., Simona Pisanti, n.u.l.l., Crescenzi, E., Bifulco, M. FEBS Lett. (2006) [Pubmed]
  16. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Jin, J., Shirogane, T., Xu, L., Nalepa, G., Qin, J., Elledge, S.J., Harper, J.W. Genes Dev. (2003) [Pubmed]
  17. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Lu, X., Nannenga, B., Donehower, L.A. Genes Dev. (2005) [Pubmed]
  18. Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. Rocha, S., Garrett, M.D., Campbell, K.J., Schumm, K., Perkins, N.D. EMBO J. (2005) [Pubmed]
  19. Claspin operates downstream of TopBP1 to direct ATR signaling towards Chk1 activation. Liu, S., Bekker-Jensen, S., Mailand, N., Lukas, C., Bartek, J., Lukas, J. Mol. Cell. Biol. (2006) [Pubmed]
  20. An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Heffernan, T.P., Simpson, D.A., Frank, A.R., Heinloth, A.N., Paules, R.S., Cordeiro-Stone, M., Kaufmann, W.K. Mol. Cell. Biol. (2002) [Pubmed]
  21. Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains. Ng, C.P., Lee, H.C., Ho, C.W., Arooz, T., Siu, W.Y., Lau, A., Poon, R.Y. J. Biol. Chem. (2004) [Pubmed]
  22. The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Castedo, M., Perfettini, J.L., Roumier, T., Yakushijin, K., Horne, D., Medema, R., Kroemer, G. Oncogene (2004) [Pubmed]
  23. DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system. Clarke, C.A., Clarke, P.R. Biochem. J. (2005) [Pubmed]
  24. Atm-dependent interactions of a mammalian chk1 homolog with meiotic chromosomes. Flaggs, G., Plug, A.W., Dunks, K.M., Mundt, K.E., Ford, J.C., Quiggle, M.R., Taylor, E.M., Westphal, C.H., Ashley, T., Hoekstra, M.F., Carr, A.M. Curr. Biol. (1997) [Pubmed]
  25. Nbs1 is required for ATR-dependent phosphorylation events. Stiff, T., Reis, C., Alderton, G.K., Woodbine, L., O'Driscoll, M., Jeggo, P.A. EMBO J. (2005) [Pubmed]
  26. Hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites. Das, K.C., Dashnamoorthy, R. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  27. p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Gottifredi, V., Karni-Schmidt, O., Shieh, S.S., Prives, C. Mol. Cell. Biol. (2001) [Pubmed]
  28. Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. Demidova, A.R., Aau, M.Y., Zhuang, L., Yu, Q. J. Biol. Chem. (2009) [Pubmed]
  29. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Alderton, G.K., Galbiati, L., Griffith, E., Surinya, K.H., Neitzel, H., Jackson, A.P., Jeggo, P.A., O'Driscoll, M. Nat. Cell Biol. (2006) [Pubmed]
  30. Cdc7-Dbf4 and the Human S Checkpoint Response to UVC. Heffernan, T.P., Unsal-Kaçmaz, K., Heinloth, A.N., Simpson, D.A., Paules, R.S., Sancar, A., Cordeiro-Stone, M., Kaufmann, W.K. J. Biol. Chem. (2007) [Pubmed]
  31. Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. Arlander, S.J., Eapen, A.K., Vroman, B.T., McDonald, R.J., Toft, D.O., Karnitz, L.M. J. Biol. Chem. (2003) [Pubmed]
  32. Characterization of the 5'flanking region of the human Chk1 gene: identification of E2F1 functional sites. Carrassa, L., Broggini, M., Vikhanskaya, F., Damia, G. Cell Cycle (2003) [Pubmed]
  33. Direct requirement for Xmus101 in ATR-mediated phosphorylation of Claspin bound Chk1 during checkpoint signaling. Yan, S., Lindsay, H.D., Michael, W.M. J. Cell Biol. (2006) [Pubmed]
  34. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Shieh, S.Y., Ahn, J., Tamai, K., Taya, Y., Prives, C. Genes Dev. (2000) [Pubmed]
  35. CHK1 kinase activity assay. Wang, Y., Wang, H. Methods Mol. Biol. (2004) [Pubmed]
  36. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. Groth, A., Lukas, J., Nigg, E.A., Silljé, H.H., Wernstedt, C., Bartek, J., Hansen, K. EMBO J. (2003) [Pubmed]
  37. Inhibition of Chk1 by activated PKB/Akt. King, F.W., Skeen, J., Hay, N., Shtivelman, E. Cell Cycle (2004) [Pubmed]
  38. ATM-dependent CHK2 activation induced by anticancer agent, irofulven. Wang, J., Wiltshire, T., Wang, Y., Mikell, C., Burks, J., Cunningham, C., Van Laar, E.S., Waters, S.J., Reed, E., Wang, W. J. Biol. Chem. (2004) [Pubmed]
  39. Human claspin is required for replication checkpoint control. Chini, C.C., Chen, J. J. Biol. Chem. (2003) [Pubmed]
  40. The relative contribution of CHK1 and CHK2 to Adriamycin-induced checkpoint. Ho, C.C., Siu, W.Y., Chow, J.P., Lau, A., Arooz, T., Tong, H.Y., Ng, I.O., Poon, R.Y. Exp. Cell Res. (2005) [Pubmed]
  41. The human decatenation checkpoint. Deming, P.B., Cistulli, C.A., Zhao, H., Graves, P.R., Piwnica-Worms, H., Paules, R.S., Downes, C.S., Kaufmann, W.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  42. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. Xu, X., Lee, J., Stern, D.F. J. Biol. Chem. (2004) [Pubmed]
  43. Cleavage-mediated activation of Chk1 during apoptosis. Matsuura, K., Wakasugi, M., Yamashita, K., Matsunaga, T. J. Biol. Chem. (2008) [Pubmed]
  44. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Zhao, H., Piwnica-Worms, H. Mol. Cell. Biol. (2001) [Pubmed]
  45. The DNA double-strand break response pathway: becoming more BRCAish than ever. Ting, N.S., Lee, W.H. DNA Repair (Amst.) (2004) [Pubmed]
  46. Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Krämer, A., Mailand, N., Lukas, C., Syljuåsen, R.G., Wilkinson, C.J., Nigg, E.A., Bartek, J., Lukas, J. Nat. Cell Biol. (2004) [Pubmed]
  47. The Involvement of Ataxia-telangiectasia Mutated Protein Activation in Nucleotide Excision Repair-facilitated Cell Survival with Cisplatin Treatment. Colton, S.L., Xu, X.S., Wang, Y.A., Wang, G. J. Biol. Chem. (2006) [Pubmed]
 
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