Both authors contributed equally to this work.
PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation
Article first published online: 18 JUL 2014
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 5, pages 879–889, October 2014
How to Cite
Jin, B., Wang, Y., Wu, C. L., Liu, K. Y., Chen, H. and Mao, Z. B. (2014), PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation. Aging Cell, 13: 879–889. doi: 10.1111/acel.12249
- Issue published online: 19 SEP 2014
- Article first published online: 18 JUL 2014
- Manuscript Accepted: 15 JUN 2014
- National Basic Research Programs of China. Grant Numbers: 2013CB530801, 2011CB966203
- Natural Science Foundation of China. Grant Number: 81170318
- senescence-associated heterochromatin foci;
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.