The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion

Mol Cell. 2001 Jun;7(6):1267-78. doi: 10.1016/s1097-2765(01)00260-x.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / genetics*
  • Cadherins / metabolism*
  • Carcinoma / pathology*
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Movement / physiology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Kidney / cytology
  • Neoplasm Invasiveness
  • RNA, Messenger / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Smad Proteins
  • Snail Family Transcription Factors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Fingers / physiology*
  • beta Catenin

Substances

  • Cadherins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Smad Proteins
  • Snail Family Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • beta Catenin