| 摘要 |
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-/- 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 transcriptional 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. |
