PKCδ Regulates Translation Initiation through PKR and eIF2α in Response to Retinoic Acid in Acute Myeloid Leukemia Cells.
PKCδ Regulates Translation Initiation through PKR and eIF2α in Response to Retinoic Acid in Acute Myeloid Leukemia Cells.
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DOI：
10.1155/2012/482905
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Lopez-Berestein G
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作者：
Ozpolat B;Akar U;Tekedereli I;Alpay SN;Barria M;Gezgen B;Zhang N;Coombes K;Kornblau S;Lopez-Berestein G
真核生物启动因子-α(eIF2-α)是翻译启动的限速步骤，在肿瘤细胞中经常被过度激活。在此，我们研究了eIF_2α在急性早幼粒细胞白血病和急性髓系白血病细胞对全反式维甲酸和三氧化二砷的调节和作用。全反式维甲酸和全反式维甲酸诱导白血病细胞(HL 60、U937和THP-1)中eIF2α的Ser-51磷酸化(失活)是通过诱导蛋白激酶C增量(PKCδ)和PKR，但不能诱导其他eIF2α激酶，如GCN2和PERK。抑制eIF_2α使参与细胞凋亡(DAP5/p97)、细胞周期(p21Waf1/Cip1)、分化(TG2)的蛋白表达减少，并诱导调控细胞增殖(c-Myc)和存活(P70S6K)的蛋白表达。PI3K/Akt/mTor通路通过PKCα/PKR轴参与eIF2δ的调控。PKCδ和p-eIF2α蛋白表达水平与47例急性髓细胞白血病患者的复发显著相关(P=0.0378)和pEIF2δ表达降低(P=0.0041)。综上所述，我们的研究首次提供了PKCδ通过诱导PKR来调控/抑制eIF2α的证据，并揭示了一种新的调控翻译启动的信号机制。
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.