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

Author

Aghajan, 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, and Huang, Jing

Subjects
Cells, Cultured, Humans, Ubiquitin-Protein Ligases, Protein-Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Cell Cycle, TOR Serine-Threonine Kinases, Protein Serine-Threonine Kinases, Genetics, 5.1 Pharmaceuticals, 1.1 Normal biological development and functioning, Underpinning research, Development of treatments and therapeutic interventions
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.

Published
2010

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

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, and Huang, Jing

Subjects
Article
Abstract

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 SCFMet30 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 SCFMet30 in vivo and in vitro, but not the closely related SCFCdc4. 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.

Published
2010

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