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Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.

Accepted version
Peer-reviewed

Change log

Authors

Mason, Bethany 
Flach, Susanne 
Teixeira, Felipe R 
Manzano Garcia, Raquel 
Rueda, Oscar M 

Abstract

In cancer, many genes are mutated by genome rearrangement, but our understanding of the functional consequences of this remains rudimentary. Here we report the F-box protein encoded by FBXL17 is disrupted in the region of the gene that encodes its substrate-binding leucine rich repeat (LRR) domain. Truncating Fbxl17 LRRs impaired its association with the other SCF holoenzyme subunits Skp1, Cul1 and Rbx1, and decreased ubiquitination activity. Loss of the LRRs also differentially affected Fbxl17 binding to its targets. Thus, genomic rearrangements in FBXL17 are likely to disrupt SCFFbxl17-regulated networks in cancer cells. To investigate the functional effect of these rearrangements, we performed a yeast two-hybrid screen to identify Fbxl17-interacting proteins. Among the 37 binding partners Uap1, an enzyme involved in O-GlcNAcylation of proteins was identified most frequently. We demonstrate that Fbxl17 binds to UAP1 directly and inhibits its phosphorylation, which we propose regulates UAP1 activity. Knockdown of Fbxl17 expression elevated O-GlcNAcylation in breast cancer cells, arguing for a functional role for Fbxl17 in this metabolic pathway.

Description

Keywords

Breast cancer, FBXL17, Genome rearrangements, O-GlcNAc, O-GlcNAcylation, Phosphorylation, UAP1, Ubiquitin, Acetylglucosamine, Breast Neoplasms, Cell Line, Tumor, DNA Breaks, F-Box Proteins, Female, HEK293 Cells, Humans, Phosphorylation, Protein Processing, Post-Translational, Sequence Deletion, Ubiquitin-Protein Ligases, Ubiquitination

Journal Title

Cell Mol Life Sci

Conference Name

Journal ISSN

1420-682X
1420-9071

Volume Title

77

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Breast Cancer Now (None)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
Cancer Research Uk (None)
Cancer Research Uk (None)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
Cancer Research UK (A27657)
Cancer Research Uk (None)
Breast Cancer Now (2013NovPhD172)
Breast Cancer Now (None)
Cancer Research Uk (None)
Breast Cancer Campaign (2014MaySP294)
Cancer Research UK (A14545)
Funding was provided by Breast Cancer Now (2013NovPhD172) to BM and HL and PAWE, and Cancer Research UK (C1023/A14545 and C1023/A9140) to PAWE; SF was supported by a Wildy Studentship from Gonville & Caius College, and the Department of Pathology, University of Cambridge. FRT was funded by a BEPE-FAPESP fellowship (2012/09241-8). The Personalised Breast Cancer Program is funded by Addenbrookes Charitable Trust, the Mark Foundation and Cancer Research UK grants to CC and JEA.