The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer
The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer
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DOI：
10.1038/sj.onc.1208303
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发表时间：
2005-02-03
期刊：
影响因子：
8
通讯作者：
Muñoz, A
中科院分区：
文献类型：
--
作者：
Gonzálex-Sancho, JM;Aguilera, O;Muñoz, A
Wnt糖蛋白通过与膜Frizzled-LRP 5/6受体复合物结合来调节体内平衡和发育。Wnt信号传导包括涉及胞质β-连环蛋白稳定、核转位和基因调控的经典途径，其充当T细胞因子（TCF）蛋白的共激活剂，以及激活Rho、Rac、JNK和PKC或调节Ca 2+水平的非经典途径。DICKKOPF-1（DKK-1）编码分泌的Wnt拮抗剂，其结合LRP 5/6并诱导其内吞作用，导致经典途径的抑制。我们发现，激活经典信号的Wnt 1或异位表达的活性β-连环蛋白，TCF 4或LRP 6突变体诱导人类DKK-1基因的转录。DKK-1基因启动子中的多个β-连环蛋白/TCF 4位点有助于这种激活。相反，Wnt 5a通过非经典途径发出信号，不激活DKK-1。北方和西方印迹研究表明，通过用锂或Wnt 3a条件培养基处理，或通过Wnt 1或β-连环蛋白的稳定表达，Wnt/β-连环蛋白途径的激活增加了DKK-1 RNA和蛋白，从而启动了负反馈环。然而，我们发现DKK-1在人结肠肿瘤中的表达降低，这表明DKK-1在这种肿瘤中起肿瘤抑制基因的作用。我们的数据表明，Wnt/β-catenin途径下调诱导DKK-1的表达，这是一种机制，在结肠癌中丢失。
Wnt glycoproteins regulate homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes. Wnt signaling includes a canonical pathway involving cytosolic beta-catenin stabilization, nuclear translocation and gene regulation, acting as a co-activator of T-cell factor (TCF) proteins, and noncanonical pathways that activate Rho, Rac, JNK and PKC, or modulate Ca2+ levels. DICKKOPF-1 (DKK-1) encodes a secreted Wnt antagonist that binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical pathway. We show that activation of canonical signaling by Wnt1 or ectopic expression of active beta-catenin, TCF4 or LRP6 mutants induces transcription of the human DKK-1 gene. Multiple beta-catenin/TCF4 sites in the DKK-1 gene promoter contribute to this activation. In contrast, Wnt5a, which signals through noncanonical pathways, does not activate DKK-1. Northern and Western blot studies show that activation of the Wnt/beta-catenin pathway by treatment with lithium or Wnt3a-conditioned medium, or by stable expression of either Wnt1 or beta-catenin, increases DKK-1 RNA and protein, thus initiating a negative feedback loop. However, we found that DKK-1 expression decreases in human colon tumors, which suggests that DKK-1 acts as a tumor suppressor gene in this neoplasia. Our data indicate that the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer.