Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin
| Autor: | Xingnan Li, Susan M. Lobo-Ruppert, W Deng, J M Ruppert |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Beta-catenin Kruppel-Like Transcription Factors Mice Transgenic Biology Kidney Zinc Finger Protein GLI1 Article Adherens junction Mice Transcription Factor 4 GLI1 Genetics Animals Epithelial–mesenchymal transition Molecular Biology Transcription factor Cells Cultured beta Catenin Cell Nucleus integumentary system Cadherin Epithelial Cells Cadherins Hedgehog signaling pathway Rats DNA-Binding Proteins Wnt Proteins Cell Transformation Neoplastic biology.protein Cancer research Snail Family Transcription Factors Signal transduction Signal Transduction Transcription Factors |
| Popis: | The Hedgehog pathway transcription factor Gli1 induces transformation of epithelial cells via induction of Snail, a repressor of E-cadherin (E-cad). E-cad is normally complexed with beta-catenin at the cell membrane. Loss of E-cad during developmental epithelial-mesenchymal transitions can switch beta-catenin from its role at adherens junctions to its role in nuclear transcription. During tumorigenesis it is unclear which pathways trigger this switch. In the current study, gain- and loss-of-function approaches identified E-cad as a selective inhibitor of transformation by Gli1, and Snail knockdown was rescued by downregulation of E-cad. Gli1 induced relocalization of beta-catenin from the cell membrane to the nucleus. The ability of wild-type or mutant alleles of E-cad to modulate transformation by Gli1 correlated with their ability to regulate localization of beta-catenin. Inhibition of Wnt-beta-catenin signaling by dominant negative Tcf4 selectively blocked in vitro transformation by Gli1. In Gli1-transgenic mice, infiltrating skin tumor cells expressed active, unphosphorylated beta-catenin. Our studies identify E-cad as a selective suppressor of transformation by Gli1 and point to the Sonic Hedgehog-Gli1 pathway as a key regulator of the beta-catenin switch in epithelial cells and cancers. |
| Databáze: | OpenAIRE |
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