发明名称 |
.BETA.-CATENIN, TCF-4, AND APC INTERACT TO PREVENT CANCER |
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.
|
申请公布号 |
CA2285701(A1) |
申请公布日期 |
1998.09.24 |
申请号 |
CA19982285701 |
申请日期 |
1998.03.20 |
申请人 |
THE JOHNS HOPKINS UNIVERSITY;UTRECHT UNIVERSITY |
发明人 |
VOGELSTEIN, BERT;KINZLER, KENNETH W.;KORINEK, VLADIMIR;SPARKS, ANDREW B.;MORIN, PATRICE J.;CLEVERS, HANS;BARKER, NICK |
分类号 |
G01N33/50;A61K31/711;A61K38/00;A61K48/00;A61P35/00;C07K14/47;C12N15/09;C12N15/12;C12Q1/68;G01N33/15;(IPC1-7):C12N15/12;A61K38/17 |
主分类号 |
G01N33/50 |
代理机构 |
|
代理人 |
|
主权项 |
|
地址 |
|