A positive feedback loop between Pim-1 kinase and HBP1 transcription factor contributes to hydrogen peroxide-induced premature senescence and apoptosis
A positive feedback loop between Pim-1 kinase and HBP1 transcription factor contributes to hydrogen peroxide-induced premature senescence and apoptosis
复制标题
Pim-1 激酶和 HBP1 转录因子之间的正反馈环有助于过氧化氢诱导的过早衰老和细胞凋亡
DOI：
10.1074/jbc.m116.768101
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发表时间：
2017-05-19
影响因子：
4.8
通讯作者：
Zhang, Xiaowei
中科院分区：
文献类型：
--
作者：
Wang, Shuya;Cao, Zhengyi;Zhang, Xiaowei
氧化应激可诱导细胞功能障碍并导致广泛的退行性改变，包括致癌、衰老和其他氧化应激相关的疾病。为了避免在氧化应激下发生癌变，细胞触发一系列的检查点反应，包括过早衰老和细胞凋亡。越来越多的证据表明，H2O2是引起氧化应激的重要原因，是细胞内信号通路的重要生理调节剂，参与调控细胞过早衰老和凋亡。然而，这一过程背后的确切机制仍有待广泛研究。在这项研究中，我们描述了Pim-1激酶在氧化应激检查点反应中的重要性。Pim-1结合并磷酸化转录因子高迁移率组盒转录因子1 (HBP1)，激活它。H2O2增强了Pim-1与HBP1的相互作用，促进HBP1的积累。反过来，HBP1在h2o2刺激的细胞中快速、选择性地上调Pim-1的表达，从而形成Pim-1-HBP1正反馈回路，调控h2o2诱导的过早衰老和细胞凋亡。此外，Pim-1-HBP1正反馈回路通过调节衰老标志物DNMT1和p16以及凋亡标志物Bax发挥作用。因此，Pim-1-HBP1轴构成了一种新的检查点通路，对抑制肿瘤发生至关重要。
Oxidative stress can induce cell dysfunction and lead to a broad range of degenerative alterations, including carcinogenesis, aging, and other oxidative stress-related conditions. To avoid undergoing carcinogenesis in response to oxidative stress, cells trigger a succession of checkpoint responses, including premature senescence and apoptosis. Increasing evidence indicates that H2O2, an important cause of oxidative stress, functions as an important physiological regulator of intracellular signaling pathways that participate in regulation of cell premature senescence and apoptosis. However, the precise mechanisms underlying this process remain to be studied extensively. In this study, we describe the importance of Pim-1 kinase in this checkpoint response to oxidative stress. Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. H2O2 enhances the interaction between Pim-1 and HBP1 and promotes HBP1 accumulation. In turn, HBP1 rapidly and selectively up-regulates Pim-1 expression in H2O2-stimulated cells, thereby creating a Pim-1-HBP1 positive feedback loop that regulates H2O2-induced premature senescence and apoptosis. Furthermore, the Pim-1-HBP1 positive feedback loop exerts its effect by regulating the senescence markers DNMT1 and p16 and the apoptosis marker Bax. The Pim-1-HBP1 axis thus constitutes a novel checkpoint pathway critical for the inhibition of tumorigenesis.