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.
Highlights
The genomes of most common epithelial cancers, such as breast cancer, are highly rearranged, but our knowledge of the rearrangements and the genes they target remains rudimentary [1]
We show that Fbxl17 interacts with Uap1, UDP-N-acetylglucosamine pyrophosphorylase 1, to regulate the overall levels of N-acetylglucosamine modification (O-GlcNAcylation) of proteins in cells
Given the leucine rich repeat (LRR) of Fbxl17 are encoded from exon 3 onwards it is likely these protein–protein interacting domains are disrupted by such rearrangements
Summary
The genomes of most common epithelial cancers, such as breast cancer, are highly rearranged, but our knowledge of the rearrangements and the genes they target remains rudimentary [1]. Have been known for some time, such as loss of the distal arm of 8p, 17p and 18q and the amplification of ERBB2 in breast cancer, but many more less-frequently occurring aberrations remain to be characterised and may be diagnostically or therapeutically important. Array-CGH detects larger scale unbalanced rearrangements and is available for large panels of tumours [9]. If such breaks fall within genes, they
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