title: Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70(S6k) and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling.
authors.affiliation: From the Graduate Program in Molecular and Cellular Biology, MS008.
authors.forename: Rory T
authors.initials: RT
authors.lastname: Coffey
authors.affiliation: the Graduate Program in Chemistry, MS015.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Shi
authors.affiliation: the Graduate Program in Biochemistry and Biophysics, MS009.
authors.forename: Marcus J C
authors.initials: MJ
authors.lastname: Long
authors.affiliation: the Department of Biology, MS009 and Rosenstiel Basic Medical Sciences Research Center, MS029, and.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Marr
authors.affiliation: the Department of Biology, MS009 and the Department of Chemistry, Brandeis University, Waltham, Massachusetts 02453-9110 hedstrom@brandeis.edu.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002219:Carbamates; C000609637:Cbz-B3A; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D014452:Ubiquitins; D001120:Arginine; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
keywords: S6 kinase; eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1); luciferase; mammalian target of rapamycin (mTOR); protein synthesis; rapamycin; translation control; ubiquilin