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Structural studies of the interaction of normal and pathological RAR with corepressors

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Author(s):
Tábata Renée Doratioto
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
Defense date:
Examining board members:
Ana Carolina Migliorini Figueira; Sandra Martha Gomes Dias; Guilherme Martins Santos; Artur Torres Cordeiro; Eduardo Magalhães Rego
Advisor: Albane Le Maire; Ana Carolina Migliorini Figueira
Abstract

The Retinoic Acid Receptor (RAR) is part of the nuclear receptors superfamily , and acts as transcription regulators of genes related to cell growth and proliferation, homeostasis and metabolism. This process is mediated by the interaction of RAR with its natural ligand, the retinoic acid. In the presence of its 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 cell proliferation . This occurs because the RAR is expressed fused to Protein Myelogenous Leukemia (PML), and behaves repressed. Until now, the most accepted explanation for this repression is that RAR-PML impairs the corepressors' dissociation and, consequently, prevents the activation of genes that are involved in these promieloid cells differentiation. In this sense, this study aimed to understand the molecular mechanism of repression in which RAR is involved. For this purpose, several tests which consist primarily on (a) expression of normal proteins (wild type) and in pathological conditions (PLM-RAR mutant) were performed together with (b) the study of the nuclear receptors and corepressores interactions , as well as, the interaction of these complexes with DNA, (c) the assembling of the NR-corepressores complexes , and (d) the structural studies of these complexes. The results obtained in this research point to a new approach in understanding how the presence of the PML-RAR protein acts in the APL. DLS and thermal stability assays point to the ability of PML-RAR to generate large organized complexes, with beta-amyloid characteristics, as identified in ThT assay. Through these results we raise the hypothesis that PML-RAR, when forming these large complexes, prevents the action of RAR in the pathways of gene regulation (interaction with DNA and co-regulators) and PML in its nuclear functions, through the sequestration of normal/wild proteins (RAR and PML) (AU)

FAPESP's process: 16/02348-2 - STRUCTURAL STUDIES OF THE INTERACTION OF NORMAL AND PATHOLOGICAL RAR AND THR WITH COREPRESSORS.
Grantee:Tábata Renée Doratioto
Support Opportunities: Scholarships in Brazil - Doctorate