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J Proteome Res. 2014 Aug 1;13(8):3783-91. doi: 10.1021/pr500387m. Epub 2014 Jul 14.

Proteomic Analysis of the EWS-Fli-1 Interactome Reveals the Role of the Lysosome in EWS-Fli-1 Turnover.

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1
†Greehey Children's Cancer Research Institute and ‡Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, United States.

Abstract

Ewing sarcoma is a cancer of bone and soft tissue in children that is characterized by a chromosomal translocation involving EWS and an Ets family transcription factor, most commonly Fli-1. EWS-Fli-1 fusion accounts for 85% of cases. The growth and survival of Ewing sarcoma cells are critically dependent on EWS-Fli-1. A large body of evidence has established that EWS-Fli-1 functions as a DNA-binding transcription factor that regulates the expression of a number of genes important for cell proliferation and transformation. However, little is known about the biochemical properties of the EWS-Fli-1 protein. We undertook a series of proteomic analyses to dissect the EWS-Fli-1 interactome. Employing a proximity-dependent biotinylation technique, BioID, we identified cation-independent mannose 6-phosphate receptor (CIMPR) as a protein located in the vicinity of EWS-Fli-1 within a cell. CIMPR is a cargo that mediates the delivery of lysosomal hydrolases from the trans-Golgi network to the endosome, which are subsequently transferred to the lysosomes. Further molecular cell biological analyses uncovered a role for lysosomes in the turnover of the EWS-Fli-1 protein. We demonstrate that an mTORC1 active-site inhibitor, torin 1, which stimulates the TFEB-lysosome pathway, can induce the degradation of EWS-Fli-1, suggesting a potential therapeutic approach to target EWS-Fli-1 for degradation.

KEYWORDS:

EWS-Fli-1; Ewing sarcoma; interactome; lysosome; protein degradation; proximity-dependent biotinylation

PMID:
24999758
PMCID:
PMC4123944
DOI:
10.1021/pr500387m
[Indexed for MEDLINE]
Free PMC Article

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