The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway

Proceedings of the National Academy of Sciences of the United States of America - Tập 96 Số 10 - Trang 5522-5527 - 1999
Michael Shtutman1, Jacob Zhurinsky1, Inbal Simcha1, Chris Albanese1, Mark D’Amico1, Richard G. Pestell1, Avri Ben-Ze′ev1
1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; and Department of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461

Tóm tắt

β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated β-catenin levels in colorectal cancer caused by mutations in β-catenin or by the adenomatous polyposis coli molecule, which regulates β-catenin degradation, result in the binding of β-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the β-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of β-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by β-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased β-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.

Từ khóa


Tài liệu tham khảo

10.1016/S0955-0674(98)80039-2

10.1016/0168-9525(93)90250-L

10.1038/382638a0

10.1016/S0092-8674(00)80112-9

10.1016/0925-4773(96)00597-7

10.1083/jcb.139.5.1325

10.1083/jcb.141.6.1433

10.1016/S0092-8674(00)81924-8

10.1016/S0092-8674(00)81925-X

10.1016/S0959-437X(97)80071-8

10.1097/00001622-199801000-00013

10.1016/S0959-437X(98)80068-3

10.1126/science.8259519

10.1126/science.8259518

10.1016/S0960-9822(98)70226-X

10.1126/science.280.5363.596

10.1126/science.272.5264.1023

10.1101/gad.10.12.1443

10.1093/emboj/17.5.1371

10.1093/emboj/16.13.3797

10.1126/science.275.5307.1787

10.1126/science.275.5307.1784

10.1126/science.275.5307.1790

10.1126/science.275.5307.1752

10.1016/S0960-9822(06)00214-4

10.1126/science.281.5382.1509

10.1126/science.274.5293.1672

10.1002/ijc.2910580420

10.1053/gast.1996.v110.pm8608874

N Arber, Y Doki, E K-H Han, A Sgambato, P Zhou, N-H Kim, T Delohery, M G Klein, P R Holt, I B Weinstein Cancer Res 57, 1569–1574 (1997).

10.1074/jbc.270.40.23589

10.1073/pnas.95.26.15339

10.1093/nar/17.15.6419

10.1128/MCB.18.6.3212

10.1038/26982

10.1038/26989

10.1073/pnas.92.7.3046

10.1016/0092-8674(94)90543-6

10.1016/S0959-437X(05)80334-X

10.1016/S0065-230X(08)60352-8

P Polakis Biochim Biophys Acta 1332, F127–F147 (1997).

10.1101/gad.12.22.3499

10.1038/379091a0

10.1074/jbc.272.21.13937

10.1073/pnas.95.8.4374

10.1128/MCB.18.8.4499

10.1002/j.1460-2075.1996.tb01050.x

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 96 Số 10

5522-5527

Thông tin tác giả