Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-03-20
1998-12-22
LeGuyader, John L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 71, 435189, 435366, C12Q 168, G01N 3353
Patent
active
058517758
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 APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or .beta.-catenin.
REFERENCES:
Curt Suplee, The Washington Post, Key Process In Cancer Is Identified, Finding May Facilitate Early Detection, Therapy, 2-4 (1997).
Bonnee Rubinfeld et al. The Journal of Biological Chemistry, "The APC Protein and E-cadherin Form Similar but Independent Complexes with .alpha.-Catenin, .beta.-Catenin, and Plakoglobin", vol. 270, No. 10, pp. 5549-5555 (1995).
J. Kawanishi et al., Molecular and Cellular Biology, "Loss of E-Cadherin-Dependent Cell-Cell Adhesion due to Mutation of the .beta.-Catenin Gene in a Human Cancer Cell Line, HSC-39" vol. 15, No. 3, pp. 1175-1181 (1995).
P.F. Robins, J. Exp. Med., "A Mutated .beta.-Catenin Gene Encodes a Melanoma-specific Antigen Recognized by Tumor Infiltrating Lymphocytes", vol. 183, pp. 1185-1192 (1996).
B. Rubinfeld et al., Science, "Association of the APC Gene Product with .beta.-Catenin", vol. 262, pp. 1731-1734 (1993).
L.K. Su et al., Science, "Association of the APC Tumor Suppressor Protein with Catenins", vol. 262, pp. 1734-1737 (1993).
Bonnee Rubinfeld et al., Science, "Binding of GSK3.beta. to the APC-.beta.-Catenin Complex and Regulation of Complex Assembly", vol. 272, pp 1023-1026 (1996).
Susan Munemitsu et al., Proc. Natl. Acad. Sci., "Regulation of intracellular .beta.-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein", vol. 92, pp. 3046-3050 (1995).
Jurgen Behrens et al., Nature, "Functional interaction of .beta.catenin with the transcription factor LEF-1" vol. 382, pp. 638-642 (1996).
Otmar Huber et al., Mech. Dev., "Nuclear localization of .beta.-catenin by interaction with transcription factor LEF-1", vol. 59, pp. 3-10 (1996).
Miranda Molenaar, Cell, "XTcf-3 Transcription Factor Mediates .beta.-Catenin-Induced Axis Formation in Xenopus Embryos", vol 86, (1996).
Barker Nick
Clevers Hans
Kinzler Kenneth W.
Korinek Vladimer
Morin Patrice J.
Johns Hopkins University
LeGuyader John L.
Schwartzman Robert
Utrecht University
LandOfFree
.beta.-catenin, Tcf-4, and APC interact to prevent cancer does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with .beta.-catenin, Tcf-4, and APC interact to prevent cancer, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and .beta.-catenin, Tcf-4, and APC interact to prevent cancer will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2045789