PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation
PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation
复制标题
Pim-1 调节细胞衰老并将 IL-6 信号传导与异染色质形成联系起来
DOI：
10.1111/acel.12249
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发表时间：
2014-10-01
期刊：
影响因子：
7.8
通讯作者：
Mao, Ze Bin
中科院分区：
文献类型：
--
作者：
Jin, Bo;Wang, Yu;Mao, Ze Bin
细胞衰老是一种增殖停止的稳定状态，它为恶性转化提供了屏障，并有助于某些化疗的抗肿瘤活性。出乎意料的是，我们发现可以促进肿瘤发生的原癌基因PIM-1的表达在衰老过程中在转录水平上被诱导。抑制PIM-1可减轻复制性和癌基因诱导的衰老。相反，PIM-1的异位表达导致过早衰老。我们还发现PIM-1与异染色质蛋白1 （HP1）在Ser93上相互作用并磷酸化。pim -1介导的HP1磷酸化增强了HP1与H3K9me3结合的能力，导致异染色质形成并抑制增殖基因，如CCNA2和PCNA。对衰老过程中PIM-1表达上调的机制分析表明，细胞衰老的关键调节因子IL-6参与了PIM-1的诱导。我们的研究表明，PIM-1是促进异染色质形成的衰老机制的关键组成部分。更重要的是，我们证明了PIM-1也是IL-6/STAT3信号传导的直接靶点，并介导细胞因子诱导的细胞衰老。
Cellular senescence is a stable state of proliferative arrest that provides a barrier against malignant transformation and contributes to the antitumor activity of certain chemotherapies. Unexpectedly, we found that the expression of proto-oncogene PIM-1, which can promote tumorigenesis, is induced at transcriptional level during senescence. Inhibition of PIM-1 alleviated both replicative and oncogene-induced senescence. Conversely, ectopic expression of PIM-1 resulted in premature senescence. We also revealed that PIM-1 interacts with and phosphorylates heterochromatin protein 1 (HP1) on Ser93. This PIM-1-mediated HP1 phosphorylation enhanced HP1's capacity to bind to H3K9me3, resulting in heterochromatin formation and suppression of proliferative genes, such as CCNA2 and PCNA. Analysis of the mechanism underlying the up-regulation of PIM-1 expression during senescence demonstrated that IL-6, a critical regulator of cellular senescence, is responsible for PIM-1 induction. Our study demonstrated that PIM-1 is a key component of the senescence machinery that contributes to heterochromatin formation. More importantly, we demonstrated that PIM-1 is also a direct target of IL-6/STAT3 signaling and mediates cytokine-induced cellular senescence.