Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence.
The 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 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 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 signalling. 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 cytokinesis, 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.
Takahashi
Akiko
A
Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
Ohtani
Naoko
N
Yamakoshi
Kimi
K
Iida
Shin-ichi
S
Tahara
Hidetoshi
H
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Ide
Toshinori
T
Saya
Hideyuki
H
Hara
Eiji
E
D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D008954:Models, Biological; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
D000098:Acetophenones; D001578:Benzopyrans; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; C085746:rottlerin; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; D000111:Acetylcysteine