Casein Kinase Iε Downregulates PI3K/Akt Signaling, Followed by Genotoxic Stress-Induced Apoptosis of Hematopoietic Cells.

Casein kinase I (CKI) ε is involved in cytokine-induced hematopoietic cell differentiation by directly interacting with the suppressor of cytokine signaling 3 (SOCS3) and/or β-catenin. Here, we show that CKIε plays an important role in hematopoietic cell survival through modifying Phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Introduction of wild-type (WT)-CKIε into murine interleukin-3 (IL-3)-dependent myeloid progenitor 32D cells increased the sensitivity to genotoxic stress, such as γ-irradiation, anti-cancer drug and cytokine-deprivation, whereas kinase-negative (KN)-CKIε suppressed it. While IL-3-induced Akt phosphorylation at Ser473 was sustained by KN-CKIε, it was attenuated by WT-CKIε. Similarly, in human promyelocytic leukemia HL-60 cells, the increase of phosphorylated Akt induced by all-trans retinoic acid was accompanied by the decrease of CKIε expression. A specific inhibitor for CKIε, CKI-7 also increased the phospho-Akt as well as phospho-PTEN (Ser380/Thr382/383; an inactive form of PTEN). Functional expression of CKIε activated PTEN by their physical association, following the decrease of phospho-Akt. The present studies suggest that the expression of CKIε downregulates PI3K/Akt signaling through PTEN, increasing the sensitivity to apoptotic signals. Taken together with the fact that CKIε is ubiquitously expressed in normal hematopoietic cells, CKIε might be critical for prevention against genotoxic stress-induced leukomogenesis. In other words, CKIε could be a candidate of the tumor suppressor in hematological malignancies as well as cancer.