Letter abstract
Nature Cell Biology 8, 1291 - 1297 (2006)
Published online: 8 October 2006 | doi:10.1038/ncb1491
Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence
Akiko Takahashi1, Naoko Ohtani1, Kimi Yamakoshi1, Shin-ichi Iida2, Hidetoshi Tahara3, Keiko Nakayama4, Keiichi I. Nakayama5, Toshinori Ide6, Hideyuki Saya2 & Eiji Hara1
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, 2, 3, 4, 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 C
(PKC) in human senescent cells. Importantly, once activated by ROS, PKC promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS–PKC signalling6, 7, 8. Sustained activation of ROS–PKC 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, 10, 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.
- Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
- Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.
- Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
- Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
- Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
- Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure 737-0112, Japan.
Correspondence to: Eiji Hara1 e-mail: hara@genome.tokushima-u.ac.jp
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