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Letter
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

1  Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.

2  Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.

3  Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.

4  Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.

5  Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

6  Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure 737-0112, Japan.

Correspondence should be addressed to Eiji Hara hara@genome.tokushima-u.ac.jp

pRbPKCdeltaWARTSThe p16INK4a cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb 1, 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 Cdelta (PKCdelta) in human senescent cells. Importantly, once activated by ROS, PKCdelta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS–PKCdelta signalling6, 7, 8. Sustained activation of ROS–PKCdelta 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.


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Nature Cell Biology
ISSN: 1465-7392
EISSN: 1476-4679
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