title: Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition.
abstract: Snail1 (Snail) and Snail2 (Slug) are transcription factors that share a similar DNA binding structure of four and five C2H2 zinc finger motifs (ZF), respectively. Both factors bind specifically to a subset of E-box motifs (E2-box: CAGGTG/CACCTG) in target promoters like the E-cadherin promoter and are key mediators of epithelial-to-mesenchymal transition (EMT). However, there are differences in the biological actions, in binding affinities to E-cadherin promoter, and in the target genes of Snail1 and Snail2, although the molecular bases are presently unknown. In particular, the role of each Snail1 and Snail2 ZF in the binding to E-boxes and in EMT induction has not been previously explored. We have approached this question by modeling Snail1 and Snail2 protein-DNA interactions and through mutational and functional assays of different ZFs. Results show that Snail1 efficient repression and binding to human and mouse E-cadherin promoter as well as EMT-inducing ability require intact ZF1 and ZF2, while for Snail2, either ZF3 or ZF4 is essential for those functions. Furthermore, the differential distribution of E2-boxes in mouse and human E-cadherin promoters also contributes to the differential Snail factor activity. These data indicate a non-equivalent role of Snail1 and Snail2 ZFs in gene repression, contributing to the elucidation of the molecular differences between these important EMT regulators.
authors.affiliation: From the Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Universidad Autónoma de Madrid (UAM), IdiPAZ, Arzobispo Morcillo, 2, 28029 Madrid, Spain and.
authors.forename: Ana
authors.initials: A
authors.lastname: Villarejo
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cortés-Cabrera
authors.forename: Patricia
authors.initials: P
authors.lastname: Molina-Ortíz
authors.forename: Francisco
authors.initials: F
authors.lastname: Portillo
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics*; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D015820:Cadherins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004247:DNA
keywords: DNA-binding Protein; E-cadherin; EMT; Repressor Protein; Zinc Finger