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Identifier 000364493
Title Μελέτη του μηχανισμού μεταγραφικής ρύθμισης του γονιδίου της μικρής GTPAΣΗΣ ΡΗΟΒ απο το μονοπάτι του μετασχηματίζοντα Αυξητικού παράγοντα β (TGFβ-1) και ο ρόλος της στις TGFβ-1- επαγώμενες αποκρίσεις του κυττάρου
Alternative Title Mechanism of the transcriptional regulation of the small GTPASE RhoB gene and its role in TFFb-1 induced cell responces.
Author Βασιλάκη, Ελευθερία
Thesis advisor Καρδάσης, Δημήτριος
Reviewer Στουρνάρας, Χρήστος
Abstract Rho proteins are characterized as molecular switches that control many cellular processes including actin and microtubule cytoskeleton organization, cell division, motility, cell adhesion, vesicular trafficking, phagocytosis and transcriptional regulation. Whereas the classical Rho GTPases are regulated by GDP/GTP cycling, in some cases transcriptional regulation, which determines the expression levels of the proteins in the cell, plays also a crucial role in their function. RhoB is the only member of the RhoA-related subfamily that is transcriptionally regulated and this regulation seems to be of high importance for its function due to the short half-life of this protein in the cell. The purpose of the present study was to investigate the mechanism of transcriptional induction of the small GTPase RhoB gene by the Transforming Growth Factor β (TGFβ-1) signaling pathway and the role of this regulation in TGFβ- 1-induced cell responses such as cell migration, epithelial to mesenchymal transition (EMT) and cell growth. We found that TGFβ-1 induces a rapid and sustained increase in the mRNA and protein levels of the RhoB gene in various cell lines including human HaCaT keratinocytes, human hepatoblastoma HepG2 cells, human prostate cancer DU145 and PC3 cells and in mouse Swiss3T3 fibroblasts. We showed that the RhoB gene is a direct transcriptional target of TGFβ-1 in HaCaT cells. We found that this regulation is specific for the RhoB gene and is facilitated by the simultaneous activation of cytoplasmic Smad and MEK/ERK pathways.The early activation of the MEK/ERK pathway is required for the recruitment of Smad3 to a novel, non-classical, Smad binding element in the proximal RhoB promoter, in a p53-dependent manner. This element is overlapping with a CCAAT box that constitutively binds Nuclear Factor Y. Mutagenesis of this site abolished the Smad and NF-Y mediated transactivation of the RhoB promoter. Using siRNA-mediated silencing, inhibition of GTPase activity by dominant negative forms and adenovirus-mediated gene transfer we established that RhoB plays an important role in TGFβ-1-induced cell migration of HaCaT, DU145 and PC3 cells. Finally, we revealed a novel mechanism of cross-talk between the classical TGFβ-1 ⁄Smad pathway and Rho GTPases in which RhoB participates in an autoinhibitory loop of the TGFβ-1/Smad pathway. This mechanism explains the negative role of RhoB in the TGFβ-1-induced epithelial to mesenchymal transition and cell growth arrest. In conclusion, the specific induction of RhoB by TGF-β and its 9 positive or negative role in TGF-β-induced cell responses indicate that RhoB could be a target for therapeutic intervention in malignant invasive tumors.
Language Greek
Subject Biochemistry
Cell growth
Epithelial -mesenchymal transition
Transcriptional regulation
Επιθήλιο- μεσεγχυματική μετατροπή
Κυτταρική ανάπτυξη
Κυτταρική μετακίνηση
Μεταγραφική Ρύθμιση
Issue date 2009-12-14
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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