Physiology and pathology of protein FEZ1: characterization of the interaction with retinoic acid receptor and evaluation of its expression in acute myeloid leukemia

Author(s)

Mariana Bertini Teixeira

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2017-08-04

Examining board members

Jörg Kobarg; Juliana Fattori; Marcelo Bispo de Jesus; Emer Suavinho Ferro

• Advisor: Jörg Kobarg; José Xavier Neto

Abstract

The protein UNC-76 was identified as an essential component for axon fasciculation and elongation in Caenorhabditis elegans. In the same line its mammalian ortholog FEZ1 presents neuronal expression and its gene knockout in mice showed hyperactivity and altered response to psychostimulants. The human paralogue FEZ2 shows ubiquitous expression and its functions seems to be related to its interaction partners. Our group previous works showed that FEZ1 is a multifunctional (hub) protein, meaning that interacts with many other proteins through its C-terminal, and structurally is natively unfolded and dimerizes through its N-terminal. Functionally, data from the literature, have shown that FEZ1 relates to neuronal development, axon outgrowth and microtubule organization/cellular transport. Hence FEZ1 is typically cytoplasmic and could act at the cytoskeleton as a dimeric and bivalent transport adaptor. This hypothesis is further supported by the observation that FEZ1 interacts and colocalizes with cytoskeleton elements and motor proteins of the kinesin family. Furthermore, evidences from the literature also demonstrated FEZ1¿s relation to nuclear proteins involved in transcription regulation and chromatin reorganization, as well as the presence of FEZ1 in nuclear extracts. This work characterized the nuclear role of FEZ1 by addressing its interaction with the retinoic acid receptor (RAR). It was demonstrated, through in vitro and cell culture experiments, the protein-receptor interaction as well as the relation of FEZ1 expression to the induction of hoxb4 gene and, therefore, a possible role for FEZ1 in a transcriptional regulation complex. Moreover, after literature evidence and also findings from our group that the super expression of FEZ1 caused the generation of "flower-like" nuclei in more than 40% cells, which is a phenotype commonly found in certain leukemias and has been associated to an increased drug resistance of the cells, this work also deepened the understanding of the expression of FEZ1 by evaluating these protein expression in leukemic patient tissue. The data provided here added new attributions to FEZ1 protein: functionally involved with retinoic acid receptor and transcription and pathologically associated to acute myeloid leukemia (AU)

• FAPESP's process: 12/00792-1 - A função fisiológica e patológica de membros da família de adaptadoras de transporte FEZ1/FEZ2 no contexto da formação de núcleos multilobulados
• Grantee: Mariana Bertini Teixeira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)