The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.
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.
Comijn
J
J
Molecular Cell Biology Unit, Department of Molecular Biology, VIB-Ghent University, B-9000, Ghent, Belgium.
Berx
G
G
Vermassen
P
P
Verschueren
K
K
van Grunsven
L
L
Bruyneel
E
E
Mareel
M
M
Huylebroeck
D
D
van Roy
F
F
D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D002277:Carcinoma / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D000074165:Zinc Finger E-box Binding Homeobox 2; D016335:Zinc Fingers / Q000502:physiology*; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D051176:beta Catenin