Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence
- 8 October 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 8 (11), 1291-1297
- https://doi.org/10.1038/ncb1491
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 pRb1,2,3,4,5 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 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 signalling6,7,8. 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 cytokinesis9,10,11, 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.This publication has 30 references indexed in Scilit:
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