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The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
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Length:
20 minutes
Released:
Dec 19, 2022
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.18.520921v1?rss=1
Authors: 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.
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.
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Podcast created by Paper Player, LLC
http://biorxiv.org/cgi/content/short/2022.12.18.520921v1?rss=1
Authors: 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.
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.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Dec 19, 2022
Format:
Podcast episode
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