PMID- 30257881 OWN - NLM STAT- MEDLINE DCOM- 20190716 LR - 20240207 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 132 IP - 24 DP - 2018 Dec 13 TI - UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice. PG - 2564-2574 LID - 10.1182/blood-2018-05-848515 [doi] AB - The mechanistic target of rapamycin (mTOR) is a central regulator of cellular proliferation and metabolism. Depending on its binding partners, mTOR is at the core of 2 complexes that either promote protein biosynthesis (mTOR complex 1; mTORC1) or provide survival and proliferation signals (mTORC2). Protein biosynthesis downstream of mTORC1 plays an important role in MYC-driven oncogenesis with translation inhibitors garnering increasing therapeutic attention. The germinal center B-cell oncogene UCHL1 encodes a deubiquitinating enzyme that regulates the balance between mTOR complexes by disrupting mTORC1 and promoting mTORC2 assembly. While supporting mTORC2-dependent growth and survival signals may contribute to its role in cancer, the suppression of mTORC1 activity is enigmatic, as its phosphorylation of its substrate 4EBP1 promotes protein biosynthesis. To address this, we used proximity-based proteomics to identify molecular complexes with which UCH-L1 associates in malignant B cells. We identified a novel association of UCH-L1 with the translation initiation complex eIF4F, the target of 4EBP1. UCH-L1 associates with and promotes the assembly of eIF4F and stimulates protein synthesis through a mechanism that requires its catalytic activity. Because of the importance of mTOR in MYC-driven oncogenesis, we used novel mutant Uchl1 transgenic mice and found that catalytic activity is required for its acceleration of lymphoma in the Emu-myc model. Further, we demonstrate that mice lacking UCH-L1 are resistant to MYC-induced lymphomas. We conclude that UCH-L1 bypasses the need for mTORC1-dependent protein synthesis by directly promoting translation initiation, and that this mechanism may be essential for MYC in B-cell malignancy. CI - (c) 2018 by The American Society of Hematology. FAU - Hussain, Sajjad AU - Hussain S AD - Department of Pediatric and Adolescent Medicine. FAU - Bedekovics, Tibor AU - Bedekovics T AD - Department of Pediatric and Adolescent Medicine. FAU - Liu, Qiuying AU - Liu Q AD - Department of Biochemistry and Molecular Biology. FAU - Hu, Wenqian AU - Hu W AUID- ORCID: 0000-0003-3577-3604 AD - Department of Biochemistry and Molecular Biology. FAU - Jeon, Haeseung AU - Jeon H AD - Department of Pediatric and Adolescent Medicine. FAU - Johnson, Sarah H AU - Johnson SH AD - Center for Individualized Medicine-Biomarker Discovery, and. FAU - Vasmatzis, George AU - Vasmatzis G AD - Center for Individualized Medicine-Biomarker Discovery, and. AD - Department of Molecular Medicine, Mayo Clinic, Rochester, MN. FAU - May, Danielle G AU - May DG AD - Enabling Technology Group, Sanford Research, Sioux Falls, SD. FAU - Roux, Kyle J AU - Roux KJ AD - Enabling Technology Group, Sanford Research, Sioux Falls, SD. AD - Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD; and. FAU - Galardy, Paul J AU - Galardy PJ AUID- ORCID: 0000-0002-0322-8882 AD - Department of Pediatric and Adolescent Medicine. AD - Department of Biochemistry and Molecular Biology. AD - Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN. LA - eng GR - P20 GM103620/GM/NIGMS NIH HHS/United States GR - R01 CA151351/CA/NCI NIH HHS/United States GR - R01 GM102203/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180926 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Neoplasm Proteins) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) RN - EC 3.4.19.12 (Uchl1 protein, mouse) SB - IM CIN - Blood. 2018 Dec 13;132(24):2529-2530. doi: 10.1182/blood-2018-10-878611. PMID: 30545891 MH - Animals MH - Cell Transformation, Neoplastic/genetics/*metabolism/pathology MH - Lymphoma, B-Cell/genetics/*metabolism/pathology MH - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism MH - Mechanistic Target of Rapamycin Complex 2/genetics/metabolism MH - Mice MH - Mice, Knockout MH - Neoplasm Proteins/genetics/*metabolism MH - Phosphorylation MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Ubiquitin Thiolesterase/genetics/*metabolism PMC - PMC6293873 COIS- Conflict-of-interest disclosure: The authors declare no competing financial interests. EDAT- 2018/09/28 06:00 MHDA- 2019/07/17 06:00 PMCR- 2018/12/13 CRDT- 2018/09/28 06:00 PHST- 2018/05/07 00:00 [received] PHST- 2018/09/16 00:00 [accepted] PHST- 2018/09/28 06:00 [pubmed] PHST- 2019/07/17 06:00 [medline] PHST- 2018/09/28 06:00 [entrez] PHST- 2018/12/13 00:00 [pmc-release] AID - S0006-4971(20)42933-7 [pii] AID - 2018/848515 [pii] AID - 10.1182/blood-2018-05-848515 [doi] PST - ppublish SO - Blood. 2018 Dec 13;132(24):2564-2574. doi: 10.1182/blood-2018-05-848515. Epub 2018 Sep 26.