Abstract
Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. Here, we report that expression of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter. SIP1 and Snail bind to partly overlapping promoter sequences and showed similar silencing effects. SIP1 can be induced by TGF-beta treatment and shows high expression in several E-cadherin-negative human carcinoma cell lines. Conditional expression of SIP1 in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercellular adhesion and simultaneously induces invasion. SIP1 therefore appears to be a promoter of invasion in malignant epithelial tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cadherins / genetics*
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Cadherins / metabolism*
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Carcinoma / pathology*
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Cell Adhesion / physiology
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Cell Line
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Cell Movement / physiology
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation / physiology
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Epithelial Cells / cytology
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Epithelial Cells / physiology
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Kidney / cytology
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Neoplasm Invasiveness
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RNA, Messenger / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Smad Proteins
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Snail Family Transcription Factors
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / physiology
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Zinc Finger E-box Binding Homeobox 2
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Zinc Fingers / physiology*
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beta Catenin
Substances
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Cadherins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Homeodomain Proteins
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RNA, Messenger
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Repressor Proteins
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Smad Proteins
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Snail Family Transcription Factors
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Trans-Activators
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Transcription Factors
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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beta Catenin