title: PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Chen Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Kai Yu
authors.initials: KY
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Ze Bin
authors.initials: ZB
authors.lastname: Mao
mesh_terms: D016922:Cellular Senescence / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D006570:Heterochromatin; D015850:Interleukin-6; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: HP1γ; IL-6; PIM-1; STAT3; senescence; senescence-associated heterochromatin foci