.beta.-catenin, Tcf-4, and APC interact to prevent cancer

US5851775A · kind A · utility

Assignees

• THE JOHNS HOPKINS UNIVERSITY · US
• Utrech University · NL

Inventors

• Nick Barker · Seattle, US
• Hans Clevers · Huis ter Heide, NL
• Kenneth W. Kinzler · Baltimore, US
• Vladimer Korinek · Praha, CZ
• Patrice J. Morin · Cockeysville, US
• Andrew Sparks · Carrboro, US
• Bert Vogelstein · Baltimore, US

Key dates

• Filing date: Mar 20, 1997
• Grant date: Dec 22, 1998
• Expiry date: Mar 20, 2017

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61K48/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The APC tumor suppressor protein binds to .beta.-catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium (hTcf-4) was cloned and characterized. hTcf-4 transactivates transcription only when associated with .beta.-catenin. Nuclei of APC.sup.-/- colon carcinoma cells were found to contain a stable .beta.-catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed .beta.-catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating .beta.-catenin/Tcf-4 transcrpitional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of .beta.-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of .beta.-catenin is critical to…