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Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor

The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyper-activation of the mTOR pathway in human cancers2, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based platform to identify small-molecule enhancers o...

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Autores principales: Aghajanyy, Mariam, Jonai, Nao, Flick, Karin, Fu, Fei, Luo, Manlin, Cai, Xiaolu, Ouni, Ikram, Pierce, Nathan, Tang, Xiaobo, Lomenick, Brett, Damoiseaux, Robert, Hao, Rui, del Moral, Pierre M., Verma, Rati, Li, Ying, Li, Cheng, Houk, Kendall N., Jung, Michael E., Zheng, Ning, Huang, Lan, Deshaies, Raymond J., Kaiser, Peter, Huang, Jing
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902569/
https://www.ncbi.nlm.nih.gov/pubmed/20581845
http://dx.doi.org/10.1038/nbt.1645
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author Aghajanyy, Mariam
Jonai, Nao
Flick, Karin
Fu, Fei
Luo, Manlin
Cai, Xiaolu
Ouni, Ikram
Pierce, Nathan
Tang, Xiaobo
Lomenick, Brett
Damoiseaux, Robert
Hao, Rui
del Moral, Pierre M.
Verma, Rati
Li, Ying
Li, Cheng
Houk, Kendall N.
Jung, Michael E.
Zheng, Ning
Huang, Lan
Deshaies, Raymond J.
Kaiser, Peter
Huang, Jing
author_facet Aghajanyy, Mariam
Jonai, Nao
Flick, Karin
Fu, Fei
Luo, Manlin
Cai, Xiaolu
Ouni, Ikram
Pierce, Nathan
Tang, Xiaobo
Lomenick, Brett
Damoiseaux, Robert
Hao, Rui
del Moral, Pierre M.
Verma, Rati
Li, Ying
Li, Cheng
Houk, Kendall N.
Jung, Michael E.
Zheng, Ning
Huang, Lan
Deshaies, Raymond J.
Kaiser, Peter
Huang, Jing
author_sort Aghajanyy, Mariam
collection PubMed
description The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyper-activation of the mTOR pathway in human cancers2, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based platform to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor of the SCF(Met30) ubiquitin ligase (SMER3). The large SCF (Skp1-Cullin-F-box) family of ubiquitin ligases performs important functions in diverse cellular processes including transcription, cell-cycle control, and immune response3. Accordingly, there would be great value in developing SCF ligase inhibitors that act by a defined mechanism to specifically inactivate ligase activity. We show here that SMER3 selectively inhibits SCF(Met30 )in vivo and in vitro, but not the closely related SCF(Cdc4). Our results demonstrate that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes, and suggest new strategies for combination therapy with rapamycin.
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spelling pubmed-29025692011-01-01 Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor Aghajanyy, Mariam Jonai, Nao Flick, Karin Fu, Fei Luo, Manlin Cai, Xiaolu Ouni, Ikram Pierce, Nathan Tang, Xiaobo Lomenick, Brett Damoiseaux, Robert Hao, Rui del Moral, Pierre M. Verma, Rati Li, Ying Li, Cheng Houk, Kendall N. Jung, Michael E. Zheng, Ning Huang, Lan Deshaies, Raymond J. Kaiser, Peter Huang, Jing Nat Biotechnol Article The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyper-activation of the mTOR pathway in human cancers2, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based platform to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor of the SCF(Met30) ubiquitin ligase (SMER3). The large SCF (Skp1-Cullin-F-box) family of ubiquitin ligases performs important functions in diverse cellular processes including transcription, cell-cycle control, and immune response3. Accordingly, there would be great value in developing SCF ligase inhibitors that act by a defined mechanism to specifically inactivate ligase activity. We show here that SMER3 selectively inhibits SCF(Met30 )in vivo and in vitro, but not the closely related SCF(Cdc4). Our results demonstrate that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes, and suggest new strategies for combination therapy with rapamycin. 2010-06-27 2010-07 /pmc/articles/PMC2902569/ /pubmed/20581845 http://dx.doi.org/10.1038/nbt.1645 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Aghajanyy, Mariam
Jonai, Nao
Flick, Karin
Fu, Fei
Luo, Manlin
Cai, Xiaolu
Ouni, Ikram
Pierce, Nathan
Tang, Xiaobo
Lomenick, Brett
Damoiseaux, Robert
Hao, Rui
del Moral, Pierre M.
Verma, Rati
Li, Ying
Li, Cheng
Houk, Kendall N.
Jung, Michael E.
Zheng, Ning
Huang, Lan
Deshaies, Raymond J.
Kaiser, Peter
Huang, Jing
Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title_full Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title_fullStr Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title_full_unstemmed Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title_short Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor
title_sort chemical genetics of tor identifies an scf family e3 ubiquitin ligase inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902569/
https://www.ncbi.nlm.nih.gov/pubmed/20581845
http://dx.doi.org/10.1038/nbt.1645
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