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Functional consequences of truncations in the Fbxl17 gene on the stability and activity of E3 ubiquitin ligase SCF (Fbx17)

Grant number: 18/09204-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2018
Effective date (End): July 31, 2019
Field of knowledge:Biological Sciences - Biochemistry
Principal researcher:Felipe Roberti Teixeira
Grantee:Joice Silva de Oliveira
Home Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

Fbxo7 is one of the 69 human F-box proteins, which interacts with SKP, Cullin and RBX to form the largest family of ubiquitin-ligases known as SCF-type E3 ubiquitin ligases. In addition to the F-box domain of interaction with SKP1, the Fbxl17 contains the LRR domain (Leucine Rich Repeat) which interacts with its substrates. The FBXL17 gene is recurrently disrupted by rearrangements in the region that encodes its LRRs, most frequently 3xLRR (called ”3LRR). From 1992 patient samples from the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) project, FBXL17 was mutated in 135. And in 746 cancer cell lines, array-CGH data showed breaks in FBXL17 in three breast lines, BT-474, HCC38, and HCC1395, and the oesophageal/gastric cardia adenocarcinoma line OE-19. As this mutation are localized in the Fbxl17-substrate interaction domain, it might causes a desiquilibrium in the ubiquitinated form of the SCF(Fbxl17) substrates, altering the cellular homeostasis. So far, there is no investigation about the consequences of this truncation in Fbxl17 in terms of SCF stability or in vitro activity. Thus, the aim of this proposal is evaluate the functionality of the SCF(Fbxl17-”3LRR) in comparison with the wild type SCF(Fbxl17). We intend to co-purify with the Fbxl17 or Fbxl17-”3LRR the SCF components (SKP1, Cullin1 and RBX1) from HEK293T and MCF7 cells transfected with these plasmids. We will also analyze the in vitro activity of these mutant and wild type complexes through ubiquitination in vitro assays. The main goal of this research plan is to understand the consequences of FBXL17 mutation in a in vitro level in order to contribuite with the understanding of the FBXL17 role in the breast cancer development.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SPAGNOL, VALENTINE; OLIVEIRA, CAIO A. B.; RANDLE, SUZANNE J.; PASSOS, PATRICIA M. S.; CORREIA, CAMILA R. S. T. B.; SIMAROLI, NATALIA B.; OLIVEIRA, JOICE S.; MEVISSEN, TYCHO E. T.; MEDEIROS, ANA CARLA; GOMES, MARCELO D.; KOMANDER, DAVID; LAMAN, HEIKE; TEIXEIRA, FELIPE ROBERTI. The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1865, n. 1 JAN 2021. Web of Science Citations: 0.

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