The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
Anerillas, C.; Mazan-Mamczarz, K.; Herman, A. B.; Munk, R.; Lam, G. K.; Calvo-Rubio, M.; Garrido, A.; Tsitsipatis, D.; Martindale, J. L.; Altes, G.; Rossi, M.; Piao, Y.; Fan, J.; Cui, C.-Y.; De, S.; Abdelmohsen, K.; de Cabo, R.; Gorospe, M.
Show abstract
Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Revisiting the Hayflick Limit: Insights from an Integrated Analysis of Changing Transcripts, Proteins, Metabolites and Chromatin 96%
- Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modulation of PKA 95%
- Cystathionine-β-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation 95%
Similar papers in this journal
- Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence. 97%
- Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen 95%
- Differentiation drives widespread rewiring of the neural stem cell chaperone network 94%
Similar papers in this journal
- Senescent cells and macrophages cooperate through a multikinase signaling network to promote intestinal transformation in Drosophila. 94%
- CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling 93%
- Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.