Casein kinase Iepsilon 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) epsilon in hematopoietic cell survival through the modification of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Introduction of wild-type (WT)-CKIepsilon into interleukin-3 (IL-3)-dependent 32D cells increased the sensitivity to genotoxic stresses, such as gamma-irradiation, etoposide, and IL-3 deprivation, whereas kinase-negative (KN)-CKIepsilon suppressed it. Contrary to KN-CKIepsilon, WT-CKIepsilon 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 CKIepsilon expression induced by all-trans retinoic acid and by the addition of a specific inhibitor for CKIepsilon in HL-60 cells. CKIepsilon seems to activate PTEN by physical interaction. These results suggest that the CKIepsilon-induced down-regulation of PI3K/Akt signaling through PTEN lead to amplified sensitivity to apoptosis. Thus, the suppression of CKIepsilon in many human leukemia cell lines may play a role in the cell immortalization.
Okamura
Atsuo
A
Hematology/Oncology, Department of Medicine, Kobe University Graduate School of Medicine 7-5-2, Chuo-ku, Kobe 650-0017, Japan.
Iwata
Nobuko
N
Tamekane
Akira
A
Yakushijin
Kimikazu
K
Nishikawa
Shinichiro
S
Hamaguchi
Miyuki
M
Fukui
Chie
C
Yamamoto
Katsuya
K
Matsui
Toshimitsu
T
D000818:Animals; D017209:Apoptosis; D048149:Casein Kinase 1 epsilon / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D048149:Casein Kinase 1 epsilon; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt