PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation

Authors

  • Bo Jin,

    1. Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing, China
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    • Both authors contributed equally to this work.
  • Yu Wang,

    1. Department of Microbiology, School of Medicine, New York University, New York, NY, USA
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    • Both authors contributed equally to this work.
  • Chen Lin Wu,

    1. Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing, China
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  • Kai Yu Liu,

    1. Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing, China
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  • Hao Chen,

    1. Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing, China
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  • Ze Bin Mao

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing, China
    • Correspondence

      Professor Zebin Mao, Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing 100191, China. Tel.: +86 10 82805138; fax: +86 10 82805138; e-mail: zbmao@bjmu.edu.cn

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Summary

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 1γ (HP1γ) on Ser93. This PIM-1-mediated HP1γ phosphorylation enhanced HP1γ'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.

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