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Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells

The target of rapamycin (TOR) kinase regulates cell growth and division. Rapamycin only inhibits a subset of TOR activities. Here we show that in contrast to the mild impact of rapamycin on cell division, blocking the catalytic site of TOR with the Torin1 inhibitor completely arrests growth without...

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Autores principales: Atkin, Jane, Halova, Lenka, Ferguson, Jennifer, Hitchin, James R., Lichawska-Cieslar, Agata, Jordan, Allan M., Pines, Jonathon, Wellbrock, Claudia, Petersen, Janni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953821/
https://www.ncbi.nlm.nih.gov/pubmed/24424027
http://dx.doi.org/10.1242/jcs.146373
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author Atkin, Jane
Halova, Lenka
Ferguson, Jennifer
Hitchin, James R.
Lichawska-Cieslar, Agata
Jordan, Allan M.
Pines, Jonathon
Wellbrock, Claudia
Petersen, Janni
author_facet Atkin, Jane
Halova, Lenka
Ferguson, Jennifer
Hitchin, James R.
Lichawska-Cieslar, Agata
Jordan, Allan M.
Pines, Jonathon
Wellbrock, Claudia
Petersen, Janni
author_sort Atkin, Jane
collection PubMed
description The target of rapamycin (TOR) kinase regulates cell growth and division. Rapamycin only inhibits a subset of TOR activities. Here we show that in contrast to the mild impact of rapamycin on cell division, blocking the catalytic site of TOR with the Torin1 inhibitor completely arrests growth without cell death in Schizosaccharomyces pombe. A mutation of the Tor2 glycine residue (G2040D) that lies adjacent to the key Torin-interacting tryptophan provides Torin1 resistance, confirming the specificity of Torin1 for TOR. Using this mutation, we show that Torin1 advanced mitotic onset before inducing growth arrest. In contrast to TOR inhibition with rapamycin, regulation by either Wee1 or Cdc25 was sufficient for this Torin1-induced advanced mitosis. Torin1 promoted a Polo and Cdr2 kinase-controlled drop in Wee1 levels. Experiments in human cell lines recapitulated these yeast observations: mammalian TOR (mTOR) was inhibited by Torin1, Wee1 levels declined and mitotic commitment was advanced in HeLa cells. Thus, the regulation of the mitotic inhibitor Wee1 by TOR signalling is a conserved mechanism that helps to couple cell cycle and growth controls.
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spelling pubmed-39538212014-05-15 Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells Atkin, Jane Halova, Lenka Ferguson, Jennifer Hitchin, James R. Lichawska-Cieslar, Agata Jordan, Allan M. Pines, Jonathon Wellbrock, Claudia Petersen, Janni J Cell Sci Research Article The target of rapamycin (TOR) kinase regulates cell growth and division. Rapamycin only inhibits a subset of TOR activities. Here we show that in contrast to the mild impact of rapamycin on cell division, blocking the catalytic site of TOR with the Torin1 inhibitor completely arrests growth without cell death in Schizosaccharomyces pombe. A mutation of the Tor2 glycine residue (G2040D) that lies adjacent to the key Torin-interacting tryptophan provides Torin1 resistance, confirming the specificity of Torin1 for TOR. Using this mutation, we show that Torin1 advanced mitotic onset before inducing growth arrest. In contrast to TOR inhibition with rapamycin, regulation by either Wee1 or Cdc25 was sufficient for this Torin1-induced advanced mitosis. Torin1 promoted a Polo and Cdr2 kinase-controlled drop in Wee1 levels. Experiments in human cell lines recapitulated these yeast observations: mammalian TOR (mTOR) was inhibited by Torin1, Wee1 levels declined and mitotic commitment was advanced in HeLa cells. Thus, the regulation of the mitotic inhibitor Wee1 by TOR signalling is a conserved mechanism that helps to couple cell cycle and growth controls. The Company of Biologists 2014-03-15 /pmc/articles/PMC3953821/ /pubmed/24424027 http://dx.doi.org/10.1242/jcs.146373 Text en © 2014. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Atkin, Jane
Halova, Lenka
Ferguson, Jennifer
Hitchin, James R.
Lichawska-Cieslar, Agata
Jordan, Allan M.
Pines, Jonathon
Wellbrock, Claudia
Petersen, Janni
Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title_full Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title_fullStr Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title_full_unstemmed Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title_short Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells
title_sort torin1-mediated tor kinase inhibition reduces wee1 levels and advances mitotic commitment in fission yeast and hela cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953821/
https://www.ncbi.nlm.nih.gov/pubmed/24424027
http://dx.doi.org/10.1242/jcs.146373
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