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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
Mason, Bethany [1] ; Flach, Susanne [2, 3] ; Teixeira, Felipe R. [4, 1] ; Garcia, Raquel Manzano [5] ; Rueda, Oscar M. [5] ; Abraham, Jean E. [5, 6, 7] ; Caldas, Carlos [5, 6, 7] ; Edwards, Paul A. W. [5, 2] ; Laman, Heike [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP - England
[2] Hutchison MRC Res Ctr, Addenbrookes Site, Hills Rd, Cambridge CB2 0XZ - England
[3] Hosp Ludwig Maximilians Univ, Dept Otolaryngol & Head Sr Neck Surg, Munich - Germany
[4] Univ Fed Sao Carlos, Dept Genet & Evolut, Sao Carlos, SP - Brazil
[5] Univ Cambridge, Dept Oncol, Canc Res UK Cambridge Inst & Canc Ctr, Li Ka Shing Ctr, Cambridge CB2 0RE - England
[6] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Breast Unit, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 2QQ - England
[7] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge CB2 2QQ - England
Número total de Afiliações: 7
Tipo de documento: Artigo Científico
Fonte: CELLULAR AND MOLECULAR LIFE SCIENCES; v. 77, n. 13, p. 2605-2620, JUL 2020.
Citações Web of Science: 0
Resumo

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. (AU)

Processo FAPESP: 12/09241-8 - Identificação de substratos da E3 ubiquitina-ligase SCF(Fbxo7) utilizando microarranjo de proteínas
Beneficiário:Felipe Roberti Teixeira
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado