title: Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase.
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.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Aghajan
authors.forename: Nao
authors.initials: N
authors.lastname: Jonai
authors.forename: Karin
authors.initials: K
authors.lastname: Flick
authors.forename: Fei
authors.initials: F
authors.lastname: Fu
authors.forename: Manlin
authors.initials: M
authors.lastname: Luo
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Cai
authors.forename: Ikram
authors.initials: I
authors.lastname: Ouni
authors.forename: Nathan
authors.initials: N
authors.lastname: Pierce
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
authors.forename: Brett
authors.initials: B
authors.lastname: Lomenick
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.forename: Rui
authors.initials: R
authors.lastname: Hao
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Del Moral
authors.forename: Rati
authors.initials: R
authors.lastname: Verma
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Kendall N
authors.initials: KN
authors.lastname: Houk
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.forename: Peter
authors.initials: P
authors.lastname: Kaiser
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
mesh_terms: D002453:Cell Cycle; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases