Casein kinase Iɛ down-regulates phospho-Akt via PTEN, following genotoxic stress-induced apoptosis in hematopoietic cells

Here, we show a functional role of casein kinase I (CKI) ɛ in hematopoietic cell survival through the modification of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Introduction of wild-type (WT)-CKIɛ into interleukin-3 (IL-3)-dependent 32D cells increased the sensitivity to genotoxic stresses, such as γ-irradiation, etoposide, and IL-3 deprivation, whereas kinase-negative (KN)-CKIɛ suppressed it. Contrary to KN-CKIɛ, WT-CKIɛ attenuated the IL-3-induced activation of Akt with the increase of PTEN activity. Similarly, the increase of Akt activation, as well as PTEN inactivation, was accompanied both by a decrease of CKIɛ expression induced by all-trans retinoic acid and by the addition of a specific inhibitor for CKIɛ in HL-60 cells. CKIɛ seems to activate PTEN by physical interaction. These results suggest that the CKIɛ-induced down-regulation of PI3K/Akt signaling through PTEN lead to amplified sensitivity to apoptosis. Thus, the suppression of CKIɛ in many human leukemia cell lines may play a role in the cell immortalization.