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

Mason, Bethany; Flach, Susanne; Teixeira, Felipe R.; Garcia, Raquel Manzano; Rueda, Oscar M.; Abraham, Jean E.; Caldas, Carlos; Edwards, Paul A. W. und Laman, Heike (2020): Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased globalO-GlcNAcylation. In: Cellular and Molecular Life Sciences, Bd. 77, Nr. 13: S. 2605-2620

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 byFBXL17is 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 inFBXL17are 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 inO-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 elevatedO-GlcNAcylation in breast cancer cells, arguing for a functional role for Fbxl17 in this metabolic pathway.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1420-682X
• Sprache: Englisch