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STRUCTURAL STUDIES OF THE INTERACTION OF NORMAL AND PATHOLOGICAL RAR AND THR WITH COREPRESSORS.

Grant number: 16/02348-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2016
Effective date (End): March 31, 2020
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Ana Carolina Migliorini Figueira
Grantee:Tábata Renée Doratioto
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil

Abstract

The Retinoic Acid Receptor (RAR) is a protein from the family of nuclear receptors that acts in the transcription of genes related to cell growth and proliferation, homeostasis and metabolism. This transcription regulation is mediated by the interaction of RAR with its natural ligand, retinoic acid. In the presence of ligand, RAR is able to recruit coactivators that are capable of interacting with other proteins from the transcription machinery. However, in the absence of ligand, RAR can repress transcription by interacting with corepressors which are multidomain proteins capable of recruiting enzymes that prevent transcription machinery to function in a particular gene. In this way many diseases are related to RAR and to nuclear receptors in general. This is the case of acute promyelocytic leukemia (APL), a pathological condition which presents a high promieloids abnormal proliferation of cells. This occurs because the RAR is expressed fused to Protein Myelogenous Leukemia (PML), which hampers the corepressors' disconnection and consequently prevents the activation of genes that are involved in these promieloids cellsdifferentiation.In this sense, this project aims to understand the mechanism of repression that RARis involved. For this purpose, there will be carried out several tests which consist primarily on (a) expression of normal proteins (wild type) and in pathological conditions (PLM-RAR mutant), (b) studying the interactions between nuclear receptors and corepressores as well as the interaction of the complex with DNA (c) assembling the NR complex with corepressores, and (d) structural studies of these complexes which will allow a better understanding of the molecular basis of RAR repression. It is important to note that these studies are directly related to the development of new drugs, since a better understanding of these proteins structure and interactions may contribute to the search for molecules able to modulate this complex and can be used to treat diseases such as APL.

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
DORATIOTO, Tábata Renée. Structural studies of the interaction of normal and pathological RAR with corepressors. 2020. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.