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 -