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- W4380363163 abstract "Abstract The RE1 Silencing Transcription Factor (REST) is a repressor of neurogenesis. Its expression is elevated in the pediatric brain tumor medulloblastoma (MB) and correlates with poor patient prognosis. RNAseq analyses of MB tumors identified significant differences in the expression of genes associated with autophagy between high- and low-REST expressing samples. Microscopy and biochemical analyses of isogenic high- and low-REST human MB cell lines confirmed REST-dependent changes in autophagy, suggesting that REST controls the process. We had previously shown that REST regulates the activity of the mammalian target of rapamycin complex 2 (mTORC2). However, whether REST controls the mTORC1 pathway, a negative regulator for autophagy, is still unknown. mTORC1 is known to block autophagy initiation by phosphorylation of UNC51-like autophagy activating kinases (ULK)1/2 and the Phosphatidyl Kinase 3 subunit C3 (PIK3C3) to prevent global expression of lysosomal and autophagy genes through Transcription Factor EB (TFEB) phosphorylation. The above findings led us to investigate if REST controls autophagy through modulation of mTORC1 activity in MBs and to understand the underlying mechanisms. Biochemical studies demonstrated that REST elevation promotes proteasomal degradation of Raptor, a key regulatory sub-unit of the mTOR1 complex, to induce autophagy. Specifically, we discovered that Raptor is a novel substrate of the deubiquitylase USP37, which we previously identified as a REST-target gene product. These data show that REST drives autophagy by silencing USP37, destabilizing Raptor, and blocking mTORC1 activity. Finally, the pharmacological blockade of autophagy caused a decline in MB cell growth in a REST-dependent manner, indicating that REST-dependent autophagy is a pro-survival mechanism in MBs." @default.
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- W4380363163 date "2023-06-01" @default.
- W4380363163 modified "2023-09-26" @default.
- W4380363163 title "MDB-33. REST AND USP37 CONTROL THE MTORC1-AUTOPHAGY AXIS IN MEDULLOBLASTOMA BY REGULATING RAPTOR DEGRADATION" @default.
- W4380363163 doi "https://doi.org/10.1093/neuonc/noad073.265" @default.
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