TY - JOUR
A2 - Studzinski, George P.
AU - Ozpolat, Bulent
AU - Akar, Ugur
AU - Tekedereli, Ibrahim
AU - Alpay, S. Neslihan
AU - Barria, Magaly
AU - Gezgen, Baki
AU - Zhang, Nianxiang
AU - Coombes, Kevin
AU - Kornblau, Steve
AU - Lopez-Berestein, Gabriel
PY - 2012
DA - 2012/07/15
TI - PKCδ Regulates Translation Initiation through PKR and eIF2α in Response to Retinoic Acid in Acute Myeloid Leukemia Cells
SP - 482905
VL - 2012
AB - Translation initiation and activity of eukaryotic initiation factor-alpha (eIF2α), the rate-limiting step of translation initiation, is often overactivated in malignant cells. Here, we investigated the regulation and role of eIF2α in acute promyelocytic (APL) and acute myeloid leukemia (AML) cells in response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the front-line therapies in APL. ATRA and ATO induce Ser-51 phosphorylation (inactivation) of eIF2α, through the induction of protein kinase C delta (PKCδ) and PKR, but not other eIF2α kinases, such as GCN2 and PERK in APL (NB4) and AML cells (HL60, U937, and THP-1). Inhibition of eIF2α reduced the expression of cellular proteins that are involved in apoptosis (DAP5/p97), cell cycle (p21Waf1/Cip1), differentiation (TG2) and induced those regulating proliferation (c-myc) and survival (p70S6K). PI3K/Akt/mTOR pathway is involved in regulation of eIF2α through PKCδ/PKR axis. PKCδ and p-eIF2α protein expression levels revealed a significant association between the reduced levels of PKCδ (P=0.0378) and peIF2 (P=0.0041) and relapses in AML patients (n=47). In conclusion, our study provides the first evidence that PKCδ regulates/inhibits eIF2α through induction of PKR in AML cells and reveals a novel signaling mechanism regulating translation initiation.
SN - 2090-3219
UR - https://doi.org/10.1155/2012/482905
DO - 10.1155/2012/482905
JF - Leukemia Research and Treatment
PB - Hindawi Publishing Corporation
KW -
ER -