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Takagaki, K. et al.

Takagaki, Katsuma, Kaminishi, Horio, Tanaka, Ohgi, Yano,

Role of Chk1 and Chk2 in Ara-C-induced differentiation of human leukemia K562 cells.

Human chronic myelogenous leukemia K562 cells are relatively resistant to the anti-metabolite cytosine arabinoside (Ara-C) and, when treated with Ara-C, they differentiate into erythrocytes without undergoing apoptosis. In this study we investigated the mechanism by which Ara-C induces K562 cells to differentiate. We first observed that Ara-C-induced differentiation of these cells is completely inhibited by the radiosensitizing agent caffeine, an inhibitor of ATM and ATR protein kinases. We next found that Ara-C activates Chk1 and Chk2 in the cells, and that the activation of Chk1, but not of Chk2, was almost completely inhibited by caffeine. Proteasome-mediated degradation of Cdc25A and phosphorylation of Cdc25C were induced by Ara-C treatment, presumably due to the activation of Chk2 and Chk1, respectively. To directly observe the effects of checkpoint kinase activation in Ara-C-induced differentiation, we suppressed Chk1 or Chk2 with the Chk1-specific inhibitor Go6976, by generating cell lines stably over-expressing dominant-negative forms of Chk2, or by siRNA-mediated knock-down of the Chk1 or the Chk2 gene. The results suggest that Ara-C-induced erythroid differentiation of K562 cells depends on both Chk1 and Chk2 pathways.[1]

References

Role of Chk1 and Chk2 in Ara-C-induced differentiation of human leukemia K562 cells. Takagaki, K., Katsuma, S., Kaminishi, Y., Horio, T., Tanaka, T., Ohgi, T., Yano, J. Genes Cells (2005) [Pubmed]

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