Reference : Caracterización funcional de Snail2 como represor de cadherina- E y como regulador de...
Dissertations and theses : Doctoral thesis
Life sciences : Biochemistry, biophysics & molecular biology
Caracterización funcional de Snail2 como represor de cadherina- E y como regulador del proceso de carcinogenésis química
Molina Ortiz, Patricia mailto [Université de Liège > > GIGA-R : Labo de génétique fonctionnelle >]
Universidad Autonoma de Madrid, ​Madrid, ​​Spain
Cano, Amparo
Portillo, Francisco
[en] Carcinogenesis ; Transcription factor ; EMT
[en] The loss of expression of intercellular adhesion protein E-cadherin is a key event in the process of epithelial-mesenchymal transition (EMT), which allows cell migration during embryonic development and invasion of tumor cells of epithelial origin (carcinomas). The transcriptional repression is one of the main mechanisms of negative regulation of E-cadherin expression in both embryonic development and during tumor progression. In recent years there has been identified different transcriptional repressors of E-cadherin gene, which in turn induce TEM, including factors the zinc finger family of Snail (Snail1 and Snail2) and ZEB (ZEB - 1 and ZEB-2) and factors of the bHLH family (E47 and Twist). Previous studies of our laboratory, comparing gene expression profiles analysis of MDCK-II cells with stable expression of Snail1, Snail2 or E47 identified different genetic programs induced by each of these factors. These differences indicate that factors Snail1, Snail2 and E47 are regulating specific genetic programs that can modify the invasive capacity, migratory, proliferative and angiogenic capacity of cells that overexpress each of these factors. These results are consistent with the functional differences between these factors during embryonic development and tumor progression.

This thesis analyzed the transcriptional mechanisms used by Snail2 for transcriptional repression of E-cadherin and its role in the induction of carcinomas in mice.
Biochemical studies showed that Snail2 required the SNAG (Snail common domain and Gfi-1) and SLUG domains for the recruitment of different co-repressors, such as mSin3A, NCoR and CtBP1, and that these co-repressors functionally interact during transcriptional repression -E-cadherin. We have also identified in Snail2 different phosphorylated residues in vivo that can regulate the activity of Snail2. Finally, functional analysis of zinc fingers revealed that while the second zinc finger is essential for the repression activity of Snail2, the fifth zinc finger has a promoter context-dependent function, by altering the Snail2 capacity of repression dependent of the promoter. These results highlight differences and similarities between the mechanisms of transcriptional repression of Snail and Snail2, supporting the functional differences between the two.

Animal model studies showed that Snail2 is essential for the survival and differentiation of keratinocytes. However, the absence of Snail2 increases the occurrence and malignant progression of carcinomas in the chemical carcinogenesis model in mouse skin. The anti-inflammatory treatment reduces malignant progression but not the emergence and growth of benign lesions. These results indicate that the absence of Snail2 during carcinogenesis promotes inflammatory processes that alter the terminal differentiation and proliferation capacity of keratinocytes by promoting carcinogenesis.

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