title: The Forkhead factor FoxQ1 influences epithelial plasticity and modulates TGF-beta1 signalling
creator: Feuerborn, Alexander
subject: ddc-570
subject: 570 Life sciences
description: Cytokines belonging to the TGF-beta family ubiquitously participate in several cellular processes and elicit cell-context specific responses in various cell types. In recent years, attention has been drawn to understand the TGF-beta1-dependent signalling cascades which alter the differentiation state of epithelial cells, especially the de-differentiation of an epithelial cell into a mesenchymal-like cell type, also referred to as EMT (epithelial-mesenchymal transition).      EMT-processes, characterized by the loss of E-cadherin expression, loss of cell-cell adhesion, and an enhanced cellular mobility have originally been described as developmental processes, essential for gastrulation and mesoderm development as well as the formation of migratory neural crest cells.    Nowadays, regardless of the original description known from developmental biology, the term ‘EMT’ is used to describe several changes of epithelial cells into fibroblastoid-like cells. Partially, this is due to the use of equivocal markers that aim to define an EMT-process. Under pathological conditions, EMT-like processes have been proposed to result in organ fibrosis and to participate in cancer progression, though this is still a matter of intense scientific debate.   Nevertheless, in-vitro as well as in-vivo studies of cytokine induced EMT-associated processes have critically contributed to the identification and characterization of factors that regulate cell plasticity and to a better understanding of the complex cytokine-induced changes in epithelial differentiation.   In this work, using high-throughput microarray techniques, the Forkhead factor FoxQ1 was identified as transcriptionally induced in a TGF-beta1-responsive cell culture model of cytokine-induced EMT-like progression, suggesting a potential impact of FoxQ1 expression in the modulation of epithelial plasticity. Subsequent RNAi-based functional analyses revealed that FoxQ1 influences epithelial plasticity by affecting the arrangement of cytoskeletal proteins, the formation of cell-cell contacts, and junction protein expression (e.g. E-cadherin and Occludin). In addition, FoxQ1 was found to regulate cell proliferation by affecting the expression of Cyclin-dependent kinases and to modify the migratory capacity of epithelial cells. In relation to TGF-beta1 signalling, this work provides evidence that FoxQ1 is induced in a Smad4-independent manner and is a putative downstream target of the transcription factor Zeb1. Transient repression as well as stable overexpression of FoxQ1 remodelled TGF-beta1-dependent alterations of cell morphology and provided evidence that FoxQ1 is a potent mediator of TGF-beta1 signalling.  Microarray-based gene expression analyses of TGF-beta1-induced epithelial cells with an impaired FoxQ1 induction indicates that FoxQ1 is a potent mediator of TGF-beta1-dependent gene expression changes, including the differential expression of transcription factors that have previously been linked to the regulation of epithelial plasticity and EMT-like progression.  
date: 2010
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/10956/1/The_Forkhead_factor_FoxQ1_influences_epithelial_plasticity_and_modulates_TGF_beta1_signalling.pdf
identifier: DOI:10.11588/heidok.00010956
identifier: urn:nbn:de:bsz:16-opus-109567
identifier:   Feuerborn, Alexander  (2010) The Forkhead factor FoxQ1 influences epithelial plasticity and modulates TGF-beta1 signalling.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/10956/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng