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Alexandre Deshière

Regulation of SNAIL1 transcription factor during Epithelial-Mesenchymal Transition in MCF10A mammary cells: Involvement of protein-kinase CK2

Published on 9 November 2010


Thesis presented November 09, 2010

Abstract:
Epithelial cells are key components for a plethora of vital functions in mammals, in particular because they can polarize and interact cohesively in a dynamic manner. These properties, grouped under the term of “Epithelial plasticity”, can manifest themselves in different ways of which the most complex is Epithelial-Mesenchymal Transition (EMT), a process that drives a cohesive epithelial cell (or a group of cells) to strongly modify its organization and its protein composition, in order to gain migratory capacities. Such morphological changes have been observed during different embryogenesis steps and are known to be under control of a series of transcription factors, some of which are also expressed during tumor progression. SNAIL1 factor (or SNAIL), of which the role is determinant in many organs setting up, is also highly expressed at the invasive edge of several carcinoma and seem to participate in cancer cells dissemination.
During the process of EMT, SNAIL expression and localization as well as its activity are under control of a complex regulation involving different post-translational modifications including phosphorylation. In this context, the goal of my thesis was to understand regulation mechanisms of SNAIL by the protein Kinase CK2 throughout EMT. This work was performed in two steps, of which the first was a biochemical characterization of SNAIL phosphorylation by CK2 and its regulation by the CK2ß regulatory subunit. In a second time, I focused on the consequences of CK2 inhibition by RNA interference in MCF10A mammary epithelial cells. This model highlighted the determining role of CK2ß in maintaining epithelial phenotype and a cohesive architecture within MCF10A cells in vitro. Taken together, all these data suggest that protein​ kinase CK2, under control of its regulatory subunit CK2ß, acts as a negative regulator of SNAIL1 transcriptional level and protein stability in order to set against EMT induction.

Keywords:
Epithelial-Mesenchymal Transition, Transcription Factor, Protein Kinase, Cell Signaling, RNA interference

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