Mitogenic signalling and the p16^INK4a–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.

pRbPKCWARTSThe p16^INK4a 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 p16^INK4a /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 signalling^{6, 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 cytokinesis^{9, 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 p16^INK4a–Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.

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