Utrecht University

Johns Hopkins University

Nick Barker

Hans Clevers

Bert Vogelstein

Kenneth W Kinzler

Andrew B Sparks

Patrice J Morin

Vladimer Korinek

Vladimar Korinek

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) a 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 APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or .beta.-catenin.

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

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 APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or .beta.-catenin.

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

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Utrecht, Netherlands

Nick Barker