Li Tony W-H, Ting Ju-Hui T, Yokoyama Noriko N, Bernstein Alla, van de Wetering Marc, Waterman Marian L
Department of Microbiology and Molecular Genetics, Rm. B240, Medical Sciences I, University of California, Irvine, Irvine, CA 92697-4025, USA.
Mol Cell Biol. 2006 Jul;26(14):5284-99. doi: 10.1128/MCB.00105-06.
Alternative promoters within the LEF1 locus produce polypeptides of opposing biological activities. Promoter 1 produces full-length LEF-1 protein, which recruits beta-catenin to Wnt target genes. Promoter 2 produces a truncated form that cannot interact with beta-catenin and instead suppresses Wnt regulation of target genes. Here we show that promoter 1 is aberrantly activated in colon cancers because it is a direct target of the Wnt pathway. T-cell factor (TCF)-beta-catenin complexes bind to Wnt response elements in exon 1 and dynamically regulate chromatin acetylation and promoter 1 activity. Promoter 2 is delimited to the intron 2/exon 3 boundary and, like promoter 1, is also directly regulated by TCF-beta-catenin complexes. Promoter 2 is nevertheless silent in colon cancer because an upstream repressor selectively targets the basal promoter leading to destabilized TCF-beta-catenin binding. We conclude that the biological outcome of aberrant LEF1 activation in colon cancer is directed by differential promoter activation and repression.
LEF1基因座内的可变启动子产生具有相反生物学活性的多肽。启动子1产生全长LEF-1蛋白，该蛋白将β-连环蛋白募集到Wnt靶基因。启动子2产生一种截短形式，其不能与β-连环蛋白相互作用，而是抑制靶基因的Wnt调节。我们在此表明，启动子1在结肠癌中异常激活，因为它是Wnt通路的直接靶点。T细胞因子（TCF）-β-连环蛋白复合物与外显子1中的Wnt反应元件结合，并动态调节染色质乙酰化和启动子1活性。启动子2定位于内含子2/外显子3边界，并且与启动子1一样，也直接受TCF-β-连环蛋白复合物调控。然而，启动子2在结肠癌中是沉默的，因为上游阻遏物选择性地靶向基础启动子，导致TCF-β-连环蛋白结合不稳定。我们得出结论，结肠癌中LEF1异常激活的生物学结果是由启动子的差异激活和抑制所决定的。
