Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing.

Autor:	Carroll B; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK bernadette.carroll@ncl.ac.uk., Nelson G; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Rabanal-Ruiz Y; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Kucheryavenko O; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Dunhill-Turner NA; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Chesterman CC; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Zahari Q; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Zhang T; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK., Conduit SE; Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., Mitchell CA; Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., Maddocks ODK; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK., Lovat P; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., von Zglinicki T; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Korolchuk VI; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK viktor.korolchuk@ncl.ac.uk.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2017 Jul 03; Vol. 216 (7), pp. 1949-1957. Date of Electronic Publication: 2017 May 31.
DOI:	10.1083/jcb.201610113
Abstrakt:	Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. We have identified that in human fibroblasts rendered senescent by stress, replicative exhaustion, or oncogene activation, mTORC1 is constitutively active and resistant to serum and amino acid starvation. This is driven in part by depolarization of senescent cell plasma membrane, which leads to primary cilia defects and a resultant failure to inhibit growth factor signaling. Further, increased autophagy and high levels of intracellular amino acids may act to support mTORC1 activity in starvation conditions. Interventions to correct these phenotypes restore sensitivity to the mTORC1 signaling pathway and cause death, indicating that persistent signaling supports senescent cell survival. (© 2017 Carroll et al.)
Databáze:	MEDLINE
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