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Characterization of the physiological and pathological functions of members of the transport adaptor family FEZ1/FEZ2

Grant number: 12/18796-3
Support Opportunities:Regular Research Grants
Duration: April 01, 2013 - March 31, 2015
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Jörg Kobarg
Grantee:Jörg Kobarg
Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil

Abstract

The proteín UNC-76 was identified as an essential component for axon fasciculation and elongation in the worm Caenorhabditis elegans. In the same way, the orthologue from mammalians FEZ1 presents expression in neuronal tissues and knockout mice for the FEZ1 gene present comportamental disorders which reflect light neurological defects. In previous work our group has shown that FEZq is a multifunctional protein (hub), able to interact with a multitude of proteins, and naturally unfolded in nature, which forms a dimer in solution. Together, these data suggest that FEZ1 acts in the cytoplasm together with citoskeleton elements and functions as a dimeric and bivalent transport adaptor. This hypothesis is reforced by the observation that FEZ1 interacts and colocalizes to microtubule structures (e.g., tubulina, CLASP2) and motor proteins of the kinesin type (e.g. KIF3A). In this context its super-expression in Hek293 cells provoked the generation of "flower-like" nuclei in more than 40% of the transfected cells. This fenomenon is known for some types of leukemia and has been associated with an increased resistence of the tumor cells to drug treatment. The human protein paralogue FEZ2, of ubiquitous expression, belongs to the FEZ protein family and we have demonstrated that it interacts with all of the same proteins as FEZ1 but in additon with another 19 proteins. This may suggest that FEZ2 is in the process of gaining new additional functions. Here we want to study the phsiologial function of FEZ1 and FEZ2 as well as the mechanistic aspects of the formation of flower-like nuclei caused by the super-expression of FEZ1 observed in certain types of cancer. To this end we will generate FEZ2 knock out mice to characterize FEZ2 function in vivo. Furthermore we will caracterize the function of FEZ1 and SCOCO in the nucleus in the context of transcription regulation, and identify other proteínas involved in the formation of "flower-like" nuclei mediated by FEZ1 over expression. We will use mass spectrometry, protein expression knock down experiments by iRNA and overexpression studies with FEZ1/2. (AU)

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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)
TEIXEIRA, MARIANA BERTINI; FIGUEIRA, ANA CAROLINA M.; FURLAN, ARIANE S.; AQUINO, BRUNO; ALBORGHETTI, MARCOS R.; LEME, ADRIANA F. PAES; WEI, LI-NA; KOBARG, JORG. Fasciculation and elongation zeta-1 protein (FEZ1) interacts with the retinoic acid receptor and participates in transcriptional regulation of the Hoxb4 gene. FEBS OPEN BIO, v. 8, n. 1, p. 4-14, . (12/18796-3, 12/00792-1, 15/11059-1)

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