The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors

13 pages, 7 figures.Transcriptional repression mechanisms have emerged as one of the crucial processes for the downregulation of E-cadherin expression during development and tumour progression. Recently, several E-cadherin transcriptional repressors have been characterized (Snail, E12/E47, ZEB-1 and SIP-1) and shown to act through an interaction with proximal E-boxes of the E-cadherin promoter. We have analyzed the participation of another member of the Snail family, Slug, and observed that it also behaves as a repressor of E-cadherin expression. Stable expression of Slug in MDCK cells leads to the full repression of E-cadherin at transcriptional level and triggers a complete epithelial to mesenchymal transition. Slug-induced repression of E-cadherin is mediated by its binding to proximal E-boxes, particularly to the E-pal element of the mouse promoter. Detailed analysis of the binding affinity of different repressors to the E-pal element indicates that Slug binds with lower affinity than Snail and E47 proteins. These results, together with the known expression patterns of these factors in embryonic development and carcinoma cell lines, support the idea that the in vivo action of the different factors in E-cadherin repression can be modulated by their relative concentrations as well as by specific cellular or tumour contexts.This work was supported by the Spanish Ministry of Science and Technology (SAF2001-2819), Instituto de Salud Carlos III (FIS01/1174) and the Comunidad Autónoma de Madrid (08.1/0055./2000). V.B. has been funded by predoctoral fellowships from the Fundación Científica de la Asociación Española contra el Cáncer (AECC) and Instituto de Salud Carlos III. H.P. is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sports.Peer reviewe

The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors

13 pages, 7 figures.Transcriptional repression mechanisms have emerged as one of the crucial processes for the downregulation of E-cadherin expression during development and tumour progression. Recently, several E-cadherin transcriptional repressors have been characterized (Snail, E12/E47, ZEB-1 and SIP-1) and shown to act through an interaction with proximal E-boxes of the E-cadherin promoter. We have analyzed the participation of another member of the Snail family, Slug, and observed that it also behaves as a repressor of E-cadherin expression. Stable expression of Slug in MDCK cells leads to the full repression of E-cadherin at transcriptional level and triggers a complete epithelial to mesenchymal transition. Slug-induced repression of E-cadherin is mediated by its binding to proximal E-boxes, particularly to the E-pal element of the mouse promoter. Detailed analysis of the binding affinity of different repressors to the E-pal element indicates that Slug binds with lower affinity than Snail and E47 proteins. These results, together with the known expression patterns of these factors in embryonic development and carcinoma cell lines, support the idea that the in vivo action of the different factors in E-cadherin repression can be modulated by their relative concentrations as well as by specific cellular or tumour contexts.This work was supported by the Spanish Ministry of Science and Technology (SAF2001-2819), Instituto de Salud Carlos III (FIS01/1174) and the Comunidad Autónoma de Madrid (08.1/0055./2000). V.B. has been funded by predoctoral fellowships from the Fundación Científica de la Asociación Española contra el Cáncer (AECC) and Instituto de Salud Carlos III. H.P. is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sports.Peer reviewe

A new role for E12/E47 in the repression ofE-cadherin expression and epithelial-mesenchymal transitions

8 páginas, 7 figuras, 1 tabla.Down-regulation ofE-cadherin expression is a determinant of tumor cell invasiveness, an event frequently associated with epithelial-mesenchymal transitions. Here we show that the mouse E12/E47 basic helix-loop-helix transcription factor (the E2A gene product) acts as a repressor of E-cadherin expression and triggers epithelial-mesenchymal transitions. The mouse E47 factor was isolated in a one-hybrid system designed to isolate repressors of the mouse E-cadherin promoter. Epithelial cells ectopically expressing E47 adopt a fibroblastic phenotype and acquire tumorigenic and migratory/invasive properties, concomitant with the suppression of E-cadherin expression. Suppression ofE-cadherin expression under stable or inducible expression of E47 in epithelial cells occurs at the transcriptional level and is dependent on the E-boxes of the E-cadherinpromoter. Interestingly, analysis of endogenous E2Aexpression in murine and human cell lines illustrated its presence in E-cadherin-deficient, invasive carcinoma cells but its absence from epithelial cell lines. This expression pattern is consistent with that observed in early mouse embryos, where E2A mRNA is absent from epithelia but strongly expressed in the mesoderm. These results implicate E12/E47 as a repressor of E-cadherinexpression during both development and tumor progression and indicate its involvement in the acquisition and/or maintenance of the mesenchymal phenotype.This work was supported by Spanish Ministry of Education and Culture Grants SAF98-0085-C03-01 (to A. C.), DGICYT-PM98-0125 (to M. A. N.), and PB97-0054 (to F. P.), Comunidad Autónoma de Madrid Grants 08.1/0024.1/99 and 08.1/0055./2000 (to A. C. and F. P.), and European Union Grant FMXR-CT96-0065 (to M. A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.Peer reviewe

Procedimiento para identificar un compuesto que inhiba la función represora de Snail

Referencia OEPM: P9901466.-- Fecha de solicitud: 01/07/1999.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid.El procedimiento consiste en añadir dicho compuesto a las células transformadas con capacidad de expresar el marcador pronóstico Snail, para después determinar la disminución o eliminación total de la capacidad de expresar dicho marcador de pronóstico en esas células transformadas. Por último, se realiza la selección de dicho compuesto para el tratamiento de la invasión y metástasis tumoral si dichas células transformadas presentan una disminución o eliminación total de la expresión de Snail (y una reversión de sus propiedades invasivas y metastásicas).Peer reviewe

Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors.

Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression

The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression

8 páginas, 8 figuras.The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial–mesenchymal transitions) during embryonic development. Epithelial–mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial–mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.This work has been supported by the Spanish Ministry of Culture (grants DGICYT-PM95- 0024 and PM98-0125 to M.A.N., SAF95-0818 and SAF98-0085-C03-01 to A.C., and PB97-0054 to F.P.), the Comunidad Autónoma de Madrid (grant 08.1/0020/97 to A.C. and M.A.N.) and the EU (grant FMRX-CT96-0065 to M.A.N).Peer reviewe

Snail, new tumoral progression marker and target protein of a new antitumoral compounds

Traducción de Patente Europea E00938837 (fecha de solicitud, 27/06/2000).-- Prioridad: ES199907019901466.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid.Marcadores de la invasión y metástasis del tumor, su uso como marcadores diagnósticos de la enfermedad y como una guía para los profesionales médicos en la selección y evaluación de los tratamientos. Se ha identificado el factor de transcripción Snail como un represor de la expresión de la E-cadherina, puesto que tiene una interacción directa con la caja E2 del elemento E-pal del promotor. La expresión ectópica del Snail en células epiteliales induce la transición epitelial-mesenquimal y la adquisición de propiedades migratorias concomitante con la inhibición de la expresión y la pérdida de otros marcadores de la diferenciación epitelial. Esta invención presenta e incluye lo siguiente: una nueva proteína diana para la identificación de nuevos compuestos antitumorales, y un nuevo marcador de la invasión y metástasis tumoral, y su aplicación como un marcador diagnóstico de la enfermedad y como una guía para los profesionales médicos en la selección y evaluación de los tratamientos.Peer reviewe

Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors

Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 −/− mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 −/− mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression