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The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer

AuthorsGonzález-Sancho, José Manuel ; Aguilera, Óscar ; García, José M.; Pendás-Franco, Natalia; Peña, Cristina; Cal, Santiago; García de Herreros, Antonio; Bonilla, Félix; Muñoz Terol, Alberto
Issue Date2005
PublisherNature Publishing Group
CitationOncogene 24(6): 1098-1103 (2005)
AbstractWnt glycoproteins regulate homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes. Wnt signaling includes a canonical pathway involving cytosolic β-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 β-catenin, TCF4 or LRP6 mutants induces transcription of the human DKK-1 gene. Multiple β-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/β-catenin pathway by treatment with lithium or Wnt3a-conditioned medium, or by stable expression of either Wnt1 or β-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/β-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer. © 2005 Nature Publishing Group All rights reserved.
Identifiersdoi: 10.1038/sj.onc.1208303
issn: 0950-9232
e-issn: 1476-5594
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