PKR activity is required for acute leukemic cell maintenance and growth
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PKR activity is required for acute leukemic cell maintenance and growth : a role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation. / Blalock, William L; Grimaldi, Cecilia; Fala, Federica; Follo, Matilde; Horn, Stefan; Basecke, Jorg; Martinelli, Giovanni; Cocco, Lucio; Martelli, Alberto M.
In: J CELL PHYSIOL, Vol. 221, No. 1, 01.10.2009, p. 232-41.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - PKR activity is required for acute leukemic cell maintenance and growth
T2 - a role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation
AU - Blalock, William L
AU - Grimaldi, Cecilia
AU - Fala, Federica
AU - Follo, Matilde
AU - Horn, Stefan
AU - Basecke, Jorg
AU - Martinelli, Giovanni
AU - Cocco, Lucio
AU - Martelli, Alberto M
N1 - Copyright 2009 Wiley-Liss, Inc.
PY - 2009/10/1
Y1 - 2009/10/1
N2 - Recent reports demonstrate that PKR is constitutively active in a variety of tumors and is required for tumor maintenance and growth. Here we report acute leukemia cell lines contain elevated levels of p-T451 PKR and PKR activity as compared to normal controls. Inhibition of PKR with a specific inhibitor, as well as overexpression of a dominant-negative PKR, inhibited cell proliferation and induced cell death. Interestingly, PKR inhibition using the specific inhibitor resulted in a time-dependent augmentation of AKT S473 and GSK-3alpha S21 phosphorylation, which was confirmed in patient samples. Increased phosphorylation of AKT and GSK-3alpha was not dependent on PI3K activity. PKR inhibition augmented levels of p-S473 AKT and p-S21/9 GSK-3alpha/beta in the presence of the PI3K inhibitor, LY294002, but was unable to augment GSK-3alpha or beta phosphorylation in the presence of the AKT inhibitor, A443654. Pre-treatment with the PKR inhibitor blocked the ability of A443654 and LY294002 to promote phosphorylation of eIF2alpha, indicating the mechanism leading to AKT phosphorylation and activation did not require eIF2alpha phosphorylation. The effects of PKR inhibition on AKT and GSK-3 phosphorylation were found to be, in part, PP2A-dependent. These data indicate that, in acute leukemia cell lines, constitutive basal activity of PKR is required for leukemic cell homeostasis and growth and functions as a negative regulator of AKT, thereby increasing the pool of potentially active GSK-3.
AB - Recent reports demonstrate that PKR is constitutively active in a variety of tumors and is required for tumor maintenance and growth. Here we report acute leukemia cell lines contain elevated levels of p-T451 PKR and PKR activity as compared to normal controls. Inhibition of PKR with a specific inhibitor, as well as overexpression of a dominant-negative PKR, inhibited cell proliferation and induced cell death. Interestingly, PKR inhibition using the specific inhibitor resulted in a time-dependent augmentation of AKT S473 and GSK-3alpha S21 phosphorylation, which was confirmed in patient samples. Increased phosphorylation of AKT and GSK-3alpha was not dependent on PI3K activity. PKR inhibition augmented levels of p-S473 AKT and p-S21/9 GSK-3alpha/beta in the presence of the PI3K inhibitor, LY294002, but was unable to augment GSK-3alpha or beta phosphorylation in the presence of the AKT inhibitor, A443654. Pre-treatment with the PKR inhibitor blocked the ability of A443654 and LY294002 to promote phosphorylation of eIF2alpha, indicating the mechanism leading to AKT phosphorylation and activation did not require eIF2alpha phosphorylation. The effects of PKR inhibition on AKT and GSK-3 phosphorylation were found to be, in part, PP2A-dependent. These data indicate that, in acute leukemia cell lines, constitutive basal activity of PKR is required for leukemic cell homeostasis and growth and functions as a negative regulator of AKT, thereby increasing the pool of potentially active GSK-3.
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Cell Survival
KW - Enzyme Activation
KW - Glycogen Synthase Kinase 3
KW - Humans
KW - Leukemia
KW - Phosphatidylinositol 3-Kinases
KW - Phosphorylation
KW - Protein Kinase Inhibitors
KW - Protein Phosphatase 2
KW - Proto-Oncogene Proteins c-akt
KW - eIF-2 Kinase
U2 - 10.1002/jcp.21848
DO - 10.1002/jcp.21848
M3 - SCORING: Journal article
C2 - 19507191
VL - 221
SP - 232
EP - 241
JO - J CELL PHYSIOL
JF - J CELL PHYSIOL
SN - 0021-9541
IS - 1
ER -