BBB seminar: Antonio García de Herreros
Snail transcriptional repressor: a key factor in the regulation of epithelial-mesenchymal transition of tumor cells
Antonio García de Herreros
Research Unit on Cellular and Molecular Biology, Municipal Institute of Medical Research (IMIM) and University Pompeu Fabra, Barcelona, Spain
The adhesion junction protein E-cadherin plays a central role in the process of epithelial morphogenesis. The protein is controlled both post-translationally through associated proteins, named catenins, and translationally. Expression of the transcriptional repressor Snail in epithelial cells downregulates E-cadherin mRNA and blocks activity of the E-cadherin promoter. Moreover, Snail overexpression in epithelial cell lines induces a remarkable change of phenotype and the acquisition of mesenchymal cell features (an epithelial-mesenchymal transition, EMT), and induction of Snail is detected in epithelial cells when they are forced to undergo EMT. In cell culture, Snail expression is dependent on the activity of NF-kappaB and ERK, two signaling pathways previously shown to be involved in EMT in several cell systems. A close analysis of the Snail promoter reveals that it is subjected to auto-regulation by Snail protein.
In addition to E-cadherin regulation, Snail represses the expression of other epithelial genes as well as activates the transcription of mesenchymal genes. Among the genes repressed, Snail blocks transcription of the gene coding for vitamin D receptor and induces tumor cells to become insensitive to this hormone, involved in the acquisition of epithelial characteristics. Therefore, Snail expression makes tumor cells refractory to vitamin D induced E-cadherin expression. With respect to gene activation, Snail promotes the expression of ZEB1, another transcriptional repressor capable to block E-cadherin expression. Snail, thus, can either block E-cadherin gene transcription directly by binding to the promoter, or indirectly by downregulating the level of an activator (vitamin D receptor) or inducing another inhibitor (ZEB1).
These results evidence that Snail is subjected to tight transcriptional regulation and suggest a role for this factor in migration of epithelial and mesenchymal cells.
Host: Anna Aragay, Department of Biomedicine
|The research of Professor Antonio García de Herreros is oriented towards the identification of the mechanisms controlling cell-cell interactions in the epithelium, and more specifically, towards the control of the function of E-cadherin, a protein essential for these contacts. His main contributions are related to the characterisation of the structure of E-cadherin-associated proteins and the understanding of the transcriptional regulation of the E-cadherin gene, describing the role of the Snail transcription factor on the repression of E-cadherin in tumor cells. He has further worked on the structure and regulation of Snail, helping to define the essential role of this protein in the acquisition of migratory properties by epithelial cells.|