Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence

Akiko Takahashi, Naoko Ohtani, Kimi Yamakoshi, Shin Ichi Iida, Hidetoshi Tahara, Keiko Nakayama, Keiichi I. Nakayama, Toshinori Ide, Hideyuki Saya, Eiji Hara

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Abstract

The p16INK4a cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb1-5 in cellular senescence. Here, we show that the p16INK4a/ Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cδ (PKCδ) in human senescent cells. Importantly, once activated by ROS, PKCδ promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCδ signalling6-8. Sustained activation of ROS-PKCδ signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis9-11, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16INK4a-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.

Original languageEnglish
Pages (from-to)1291-1297
Number of pages7
JournalNature Cell Biology
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 1 2006

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S. I., Tahara, H., Nakayama, K., ... Hara, E. (2006). Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biology, 8(11), 1291-1297. https://doi.org/10.1038/ncb1491