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

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

  • Nat Biotechnol. 2010 Jul;28(7):738-42. doi: 10.1038/nbt.1645.
Mariam Aghajan 1,  Nao Jonai,  Karin Flick,  Fei Fu,  Manlin Luo,  Xiaolu Cai,  Ikram Ouni,  Nathan Pierce,  Xiaobo Tang,  Brett Lomenick,  Robert Damoiseaux,  Rui Hao,  Pierre M Del Moral,  Rati Verma,  Ying Li,  Cheng Li,  Kendall N Houk,  Michael E Jung,  Ning Zheng,  Lan Huang,  Raymond J Deshaies,  Peter Kaiser,  Jing Huang
Affiliations

Affiliation

  • 1 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California, USA.
PMID: 20581845 DOI: 10.1038/nbt.1645
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.

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