mTOR under stress

Alexander Martin Heberle

mTOR under stress

Onderzoeksoutput: Thesis fully internal (DIV)

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Samenvatting

Het ‘mechanistic/ mammalian target of rapamycin complex 1’ (mTORC1) is een belangrijke metabole regulator die signalen van aminozuren, groeifactoren en energie integreert om het cel metabolisme te controleren. Het mTORC1 kinase versterkt vrijwel alle anabole processen en remt katabolisme, om celgroei te stimuleren. Gedurende stress bevordert mTORC1 ook cel overleving. Daarom is mTORC1 activiteit nodig om onder gunstige en ongunstige omstandigheden respectievelijk groei en overleving te faciliteren. Hyperactiviteit van mTORC1 resulteert echter in celdood doordat metabolisme en groei worden losgekoppeld van de regulatoire signalen. Vandaar dat mTORC1 activiteit nauwkeurig geregeld moet worden om (i) anabole processen en celgroei te bevorderen wanneer er voldoende voedingsstoffen aanwezig zijn, en (ii) anabole en katabole processen te balanceren om overleving van de cel bij stress mogelijk te maken. Terwijl de moleculaire mechanismen die anabole signalen naar mTORC1 mediëren uitgebreid beschreven zijn, zijn mechanistische studies over stress-signalering naar mTORC1 en mTORC1-gemedieerde modificatie van cel metabolisme relatief schaars. Dit proefschrift richt zich op de mechanismen die het evenwicht regelen van mTORC1 activiteit en functie gedurende stress. We identificeren nieuwe mechanismen die het evenwicht tussen anabole en catabole processen regelen om tijdens stress cel overleving te ondersteunen. Onze inzichten suggereren een belangrijke ‘Achilleshiel’, wat een therapeutisch doel kan dienen in de behandeling van kanker.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Thedieck, Kathrin, Supervisor Grellscheid, Sushma-Nagaraja, Co-supervisor, Externe Persoon
Datum van toekenning	20-feb.-2019
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Gedrukte ISBN's	9789463235013
Elektronische ISBN's	9789463235020
Status	Published - 2019

Toegang tot document

Chapter 2Final publisher's version, 1,55 MB
Chapter 3Final publisher's version, 4,79 MB
Chapter 5 Publisher's versionFinal publisher's version, 3,93 MB
AcknowledgementsFinal publisher's version, 317 KB
Curriculum vitae and publicationsFinal publisher's version, 432 KB

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Citeer dit

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title = "mTOR under stress",

abstract = "The mechanistic/ mammalian target of rapamycin complex 1 (mTORC1) is a metabolic master regulator which integrates amino acid, growth factor, and energy signals to control cellular metabolism. mTORC1 kinase enhances virtually all anabolic processes and inhibits catabolism to promote cell growth. Under stress, mTORC1 also promotes cell survival. Therefore, mTORC1 activity is needed both under favorable and unfavorable conditions to enable growth and survival, respectively. However, mTORC1 hyperactivity leads to cell death due to uncoupling of metabolism and growth from regulatory inputs. Hence, mTORC1 activity has to be finely tuned to (i) promote anabolic processes and cell growth when nutrients are sufficient, and (ii) balance anabolic and catabolic processes and allow cell survival under stress. While the molecular mechanisms mediating anabolic inputs to mTORC1 have been reported in much detail, mechanistic studies on stress-signaling to mTORC1 and mTORC1-mediated adaptation of cellular metabolism are comparably scarce. This thesis centers on the mechanisms which balance mTORC1 activity and function under stress. We identified novel mechanisms that balance anabolic and catabolic processes to sustain survival under stress. Our findings suggest a novel Achilles heel, which can be targeted in cancer.",

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N2 - The mechanistic/ mammalian target of rapamycin complex 1 (mTORC1) is a metabolic master regulator which integrates amino acid, growth factor, and energy signals to control cellular metabolism. mTORC1 kinase enhances virtually all anabolic processes and inhibits catabolism to promote cell growth. Under stress, mTORC1 also promotes cell survival. Therefore, mTORC1 activity is needed both under favorable and unfavorable conditions to enable growth and survival, respectively. However, mTORC1 hyperactivity leads to cell death due to uncoupling of metabolism and growth from regulatory inputs. Hence, mTORC1 activity has to be finely tuned to (i) promote anabolic processes and cell growth when nutrients are sufficient, and (ii) balance anabolic and catabolic processes and allow cell survival under stress. While the molecular mechanisms mediating anabolic inputs to mTORC1 have been reported in much detail, mechanistic studies on stress-signaling to mTORC1 and mTORC1-mediated adaptation of cellular metabolism are comparably scarce. This thesis centers on the mechanisms which balance mTORC1 activity and function under stress. We identified novel mechanisms that balance anabolic and catabolic processes to sustain survival under stress. Our findings suggest a novel Achilles heel, which can be targeted in cancer.

AB - The mechanistic/ mammalian target of rapamycin complex 1 (mTORC1) is a metabolic master regulator which integrates amino acid, growth factor, and energy signals to control cellular metabolism. mTORC1 kinase enhances virtually all anabolic processes and inhibits catabolism to promote cell growth. Under stress, mTORC1 also promotes cell survival. Therefore, mTORC1 activity is needed both under favorable and unfavorable conditions to enable growth and survival, respectively. However, mTORC1 hyperactivity leads to cell death due to uncoupling of metabolism and growth from regulatory inputs. Hence, mTORC1 activity has to be finely tuned to (i) promote anabolic processes and cell growth when nutrients are sufficient, and (ii) balance anabolic and catabolic processes and allow cell survival under stress. While the molecular mechanisms mediating anabolic inputs to mTORC1 have been reported in much detail, mechanistic studies on stress-signaling to mTORC1 and mTORC1-mediated adaptation of cellular metabolism are comparably scarce. This thesis centers on the mechanisms which balance mTORC1 activity and function under stress. We identified novel mechanisms that balance anabolic and catabolic processes to sustain survival under stress. Our findings suggest a novel Achilles heel, which can be targeted in cancer.

M3 - Thesis fully internal (DIV)

SN - 9789463235013

PB - University of Groningen

CY - [Groningen]

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