Protein Kinase C-δ mediates down-regulation of heterogeneous nuclear ribonucleoprotein K protein: involvement in apoptosis induction
Protein Kinase C-δ mediates down-regulation of heterogeneous nuclear ribonucleoprotein K protein: involvement in apoptosis induction
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DOI：
10.1016/j.yexcr.2009.09.005
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发表时间：
2009-11-15
影响因子：
3.7
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
--
作者：
Gao, Feng-Hou;Wu, Ying-Li;Chen, Guo-Qiang
我们先前报道了喜树碱类似物NSC 606985通过蛋白激酶C δ（Delta PKC-delta）的蛋白水解激活诱导急性髓性白血病（AML）细胞凋亡。通过亚细胞蛋白质组分析，异质核核糖核蛋白K（hnRNP K）被确定为显着下调在NSC 606985处理的白血病NB 4细胞。HnRNP K是DNA、RNA和转录或翻译分子的对接蛋白，参与了许多涉及基因表达调控的过程。然而，hnRNP K减少的分子机制及其在细胞凋亡中的作用仍不清楚。在本研究中，我们发现，随着Delta PKC-δ的出现，hnRNP K蛋白在NSC 606985、阿霉素、三氧化二砷和紫外线诱导的细胞凋亡中显著下调。我们进一步提供证据表明，在细胞凋亡过程中，Delta PKC-δ介导了hnRNP K蛋白的下调：PKC-δ抑制剂可以挽救hnRNP K的减少;在PKC-δ缺陷的凋亡KG 1a细胞中，hnRNP K未能减少;在U937 T细胞中条件诱导Delta PKC-δ直接下调hnRNP K蛋白。此外，蛋白酶体抑制剂还抑制了凋亡诱导剂对hnRNP K蛋白的下调和Delta PKC-δ的条件性表达。更有趣的是，用siRNA转染抑制hnRNP K显著诱导细胞凋亡。据我们所知，这是第一次证明蛋白水解激活的PKC-δ以蛋白酶体依赖的方式下调hnRNP K蛋白，其在细胞凋亡诱导中起重要作用。(C)2009年由Elsevier Inc.出版
We reported previously that NSC606985, a camptothecin analogue, induces apoptosis of acute myeloid leukemia (AML) cells through proteolytic activation of protein kinase C delta (Delta PKC-delta). By subcellular proteome analysis, heterogeneous nuclear ribonucleoprotein K (hnRNP K) was identified as being significantly down-regulated in NSC606985-treated leukemic NB4 cells. HnRNP K, a docking protein for DNA, RNA, and transcriptional or translational molecules, is implicated in a host of processes involving the regulation of gene expression. However, the molecular mechanisms of hnRNP K reduction and its roles during apoptosis are still not understood. in the present study, we found that, following the appearance of the Delta PKC-delta, hnRNP K protein was significantly down-regulated in NSC606985, doxorubicin, arsenic trioxide and ultraviolet-induced apoptosis. We further provided evidence that Delta PKC-delta mediated the down-regulation of hnRNP K protein during apoptosis: PKC-delta inhibitor could rescue the reduction of hnRNP K; hnRNP K failed to be decreased in PKC-delta-deficient apoptotic KG1a cells; conditional induction of Delta PKC-delta in U937T cells directly down-regulated hnRNP K protein. Moreover, the proteasome inhibitor also inhibited the down-regulation of hnRNP K protein by apoptosis inducer and the conditional expression of Delta PKC-delta. More intriguingly, the suppression of hnRNP K with siRNA transfection significantly induced apoptosis. To our knowledge, this is the first demonstration that proteolytically activated PKC-delta down-regulates hnRNP K protein in a proteasome-dependent manner, which plays an important role in apoptosis induction. (C) 2009 Published by Elsevier Inc.