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Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase

Aghajan, Mariam and Jonai, Nao and Flick, Karin and Fu, Fei and Luo, Manlin and Cai, Xiaolu and Ouni, Ikram and Pierce, Nathan W. and Tang, Xiaobo and Lomenick, Brett and Damoiseaux, Robert D. and Hao, Rui and del Moral, Pierre M. and Verma, Rati and Li, Ying and Li, Cheng and Houk, Kendall N. and Jung, Michael E. and Zheng, Ning and Huang, Lan and Deshaies, Raymond J. and Kaiser, Peter and Huang, Jing (2010) Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase. Nature Biotechnology, 28 (7). pp. 738-742. ISSN 1087-0156. PMCID PMC2902569. https://resolver.caltech.edu/CaltechAUTHORS:20100802-150048893

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Abstract

The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyperactivation of the mammalian TOR (mTOR) pathway in human cancers, strategies to enhance TOR pathway inhibition are needed. We used a yeast-based screen to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor (SMER3) of the Skp1-Cullin-F-box (SCF)^(Met30) ubiquitin ligase, a member of the SCF E3-ligase family, which regulates diverse cellular processes including transcription, cell-cycle control and immune response. We show here that SMER3 inhibits SCF^(Met30) in vivo and in vitro, but not the closely related SCF^(Cdc4). Furthermore, we demonstrate that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and show evidence for SMER3 directly binding to Met30. Our results show that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes.


Item Type:Article
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http://dx.doi.org/10.1038/nbt.1645 DOIArticle
http://www.nature.com/nbt/journal/v28/n7/abs/nbt.1645.htmlPublisherArticle
http://rdcu.be/c2EjPublisherFree ReadCube access
http://www.nature.com/nbt/journal/v28/n7/extref/nbt.1645-S1.pdfPublisherSupplementary Information
http://www.nature.com/nbt/journal/v28/n7/extref/nbt.1645-S2.xlsPublisherSupplementary Information
http://www.nature.com/nbt/journal/v28/n7/extref/nbt.1645-S3.xlsPublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902569/PubMed CentralArticle
ORCID:
AuthorORCID
Houk, Kendall N.0000-0002-8387-5261
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2010 Nature Publishing Group. Received 9 March; accepted 9 May; published online 27 June 2010. We are grateful for grant support from the American Cancer Society and the U.S. National Institutes of Health and for traineeship support of M.A. and B.L. by the NIH UCLA Chemistry−Biology Interface Predoctoral Training Program. N.Z. and R.J.D. are investigators of the Howard Hughes Medical Institute. We thank D. Skowyra (Saint Louis University) and M. Tyers (University of Edinburgh, UK) for their generous gifts of bacculo virus constructs and anti-Met4 antibody, respectively. We also thank J. Salcedo (Roche Diagnostics Corporation) for support toward differential scanning fluorimetry experiments. Author Contributions: Figure 1a, M.A. and R.D.; 1b, F.F. and M.L.; 1c, C.L. and J.H.; 2a, N.J.; 2b, N.J. and R.H.; 2c, K.F.; 2d,e, I.O. and N.P.; 3a, K.F.; 3b, K.F. and L.H.; 3c, K.F.; 3d, N.J.; 3e, M.A.; Table 1, X.T., M.A. and P.M.d.M.; X.C., B.L., R.V., Y.L., K.N.H., M.E.J. and N.Z. contributed new reagents and analysis; all authors discussed data; M.A., F.F., M.E.J., R.J.D., P.K. and J.H. wrote the paper with input from all authors.
Funders:
Funding AgencyGrant Number
American Cancer Society UNSPECIFIED
UCLAUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Roche Diagnostics Corporation UNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC2902569
Record Number:CaltechAUTHORS:20100802-150048893
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100802-150048893
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:19248
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Aug 2010 18:43
Last Modified:03 Oct 2019 01:54

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