Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation
| Autor: | Matthias H. Kraus, W Deng, Xingnan Li, J M Ruppert, Clinton D. Nail, Susan M. Lobo-Ruppert, Sarah K. Bailey |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Skin Neoplasms Molecular Sequence Data Kruppel-Like Transcription Factors Snail medicine.disease_cause Zinc Finger Protein GLI1 Article Mice Downregulation and upregulation GLI1 biology.animal parasitic diseases Genetics medicine Animals RNA Small Interfering Molecular Biology Skin Hyperplasia biology integumentary system Base Sequence Cell growth fungi Cell Cycle Cell cycle Hedgehog signaling pathway Cell biology Mice Inbred C57BL Cell Transformation Neoplastic Carcinoma Basal Cell SNAI1 biology.protein Snail Family Transcription Factors Carcinogenesis Transcription Factors |
| Popis: | Gli family members mediate constitutive Hedgehog signaling in the common skin cancer, basal cell carcinoma (BCC). Snail/Snai1 is rapidly induced by Gli1 in vitro, and is coexpressed with Gli1 in human hair follicles and skin tumors. In the current study, we generated a dominant-negative allele of Snail, SnaZFD, composed of the zinc-finger domain and flanking sequence. In promoter–reporter assays, SnaZFD blocked the activity of wild-type Snail on the E-cadherin promoter. Snail loss-of-function mediated by SnaZFD or by one of several short hairpin RNAs inhibited transformation of RK3E epithelial cells by Gli1. Conversely, enforced expression of Snail promoted transformation in vitro by Gli1, but not by other genes that were tested, including Notch1, ErbB2, and N-Ras. As observed for Gli1, wild-type Snail repressed E-cadherin in RK3E cells and induced blebbing of the cytoplasmic membrane. Induction of a conditional Gli1 transgene in the basal keratinocytes of mouse skin led to rapid upregulation of Snail transcripts and to cell proliferation in the interfollicular epidermis. Established Gli1-induced skin lesions exhibited molecular similarities to BCC, including loss of E-cadherin. The results identify Snail as a Gli1-inducible effector of transformation in vitro, and an early Gli1-responsive gene in the skin. |
| Databáze: | OpenAIRE |
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