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Claudin-1 is an integral membrane protein component of tight junctions. The Snail family of transcription factors are repressors that play a central role in the epithelial-mesenchymal transition, a process that occurs during cancer progression. Snail and Slug members are direct repressors of E-cadherin and act by binding to the specific E-boxes of its proximal promoter. In the present study, we demonstrate that overexpression of Slug or Snail causes a decrease in transepithelial electrical resistance. Overexpression of Slug and Snail in MDCK (Madin-Darby canine kidney) cells down-regulated Claudin-1 at protein and mRNA levels. In addition, Snail and Slug are able to effectively repress human Claudin-1-driven reporter gene constructs containing the wild-type promoter sequence, but not those with mutations in two proximal E-box elements. We also demonstrate by band-shift assay that Snail and Slug bind to the E-box motifs present in the human Claudin-1 promoter. Moreover, an inverse correlation in the levels of Claudin-1 and Slug transcripts were observed in breast cancer cell lines. E-box elements in the Claudin-1 promoter were found to play a critical negative regulatory role in breast cancer cell lines that expressed low levels of Claudin-1 transcript. Significantly, in invasive human breast tumours, high levels of Snail and Slug correlated with low levels of Claudin-1 expression. Taken together, these results support the hypothesis that Claudin-1 is a direct downstream target gene of Snail family factors in epithelial cells.

Original publication

DOI

10.1042/bj20050591

Type

Journal article

Journal

The Biochemical journal

Publication Date

03/2006

Volume

394

Pages

449 - 457

Addresses

Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. ofeliamartinez@ub.edu

Keywords

Cell Line, Fibroblasts, Epithelial Cells, Animals, Dogs, Humans, Breast Neoplasms, Membrane Proteins, Transcription Factors, Repressor Proteins, Down-Regulation, Protein Binding, Molecular Sequence Data, Promoter Regions, Genetic, Claudin-1, Snail Family Transcription Factors