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


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

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

Funder: Wildy Fellowship Department of Pathology


Funder: Addenbrooke's Charitable Trust, Cambridge University Hospitals; doi: http://dx.doi.org/10.13039/501100002927


Funder: The Mark Foundation

Keywords
Original Article, FBXL17, Genome rearrangements, O-GlcNAcylation, O-GlcNAc, UAP1, Ubiquitin, Phosphorylation, Breast cancer
Journal Title
Cellular and Molecular Life Sciences
Conference Name
Journal ISSN
1420-682X
1420-9071
Volume Title
77
Publisher
Springer International Publishing
Sponsorship
Breast Cancer Now (2013NovPhD172, 2013NovPhD172, 2013NovPhD172)
Cancer Research UK (C1023/A14545)
Cancer Research UK (C1023/A9140)
BEPE-FAPESP (2012/09241-8)