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

被引:1902
作者
Shtutman, M
Zhurinsky, J
Simcha, I
Albanese, C
D'Amico, M
Pestell, R
Ben-Ze'ev, A [1 ]
机构
[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel
[2] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[3] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA
关键词
D O I
10.1073/pnas.96.10.5522
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
beta-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 beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-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 beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of beta-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 beta-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased beta-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.
引用
收藏
页码:5522 / 5527
页数:6
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