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Functional characterization of the E3 ubiquitin-ligase SCF(Fbxo7/PARK15) in the oncogenic Wnt pathway and mitochondrial homeostasis


Fbxo7 is one of the 69 human F-box proteins, which are the specificity factors for the largest family of ubiquitin-ligases known as SCF-type E3 ubiquitin ligases. Fbxo7 is a F-box only protein (Fbxo) of clinical importance having been associated with two major diseases, cancer and Parkinson's disease (PD). It regulates the cell cycle and it is expressed in tumors of epithelial lineages (colorectal adenocarcinoma and lung cancer), but not in the corresponding normal tissues. Four disease-associated mutations in FBXO7/PARK15 (T22M, R378G, R481C e R498X) have been identified in patients with PD. Despite it being the fifth most abundant SCF-type ligase expressed in cultured cells, relatively few Fbxo7 ubiquitinated substrates have been identified, and none would explain its role in human diseases. Recently, we have applied a highthroghput ubiquitination in vitro assay with purified SCF(Fbxo7) and protoarrays to identify new substrates. A total of 366 new potential Fbxo7 substrates were found and 3 of them associated to Wnt pathway, mitochondrial homeostasis and NF-ºB signaling (GSK3², TOMM20 e UXT respectively) were validated. We have found that the ubiquitination of GSK3² inhibited its activity and promoted activation of Wnt pathway, but we still don't know how it worked. Also, SCF(Fbxo7) introduced K63 linkage in TOMM20, which is a signal of functional regulation, but the consequences in mitochondrial homeostasis and mithophagy were not evaluated. We propose here to determine the functional relationship between SCF(Fbxo7) and their substrates TOMM20 and GSK3² related to mitochondrial homeostasis (mithophagy) and Wnt pathway, respectively. The main goal of this research proposal is understand the role of Fbxo7 in Cancer and Parkinson's disease. (AU)

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(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.
MEDEIROS, ANA CARLA; SOARES, CLAUDIA S.; COELHO, PRISCILA O.; VIEIRA, NICHELLE A.; BAQUI, MUNIRA M. A.; TEIXEIRA, FELIPE R.; GOMES, MARCELO D. DNA damage response signaling does not trigger redistribution of SAMHD1 to nuclear foci. Biochemical and Biophysical Research Communications, v. 499, n. 4, p. 790-796, MAY 23 2018. Web of Science Citations: 1.

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