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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

Oncogene volume 24, pages 1098–1103 (2005)Cite this article

Abstract

Wnt 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.

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Acknowledgements

We thank Dr Pieter de Jong for the human BAC clone and Robin Rycroft for his valuable assistance in the preparation of the English manuscript. This study was supported by Grants from Fundación de Investigación Médica Mutua Madrileña, Fundación Científica de la Asociación Española contra el Cáncer, Instituto de Salud Carlos III (FIS03-C03/10) and Ministerio de Educación y Ciencia (SAF01-2291) of Spain.

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Author notes

  1. José Manuel González-Sancho and Oscar Aguilera: These authors contributed equally to this work

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, E-28029, Madrid, Spain

    José Manuel González-Sancho, Oscar Aguilera, Natalia Pendás-Franco & Alberto Muñoz

  2. Hospital Universitario Puerta de Hierro, E-28035, Madrid, Spain

    José Miguel García, Cristina Peña & Félix Bonilla

  3. Departamento de Bioquímica y Biologia Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, E-33006, Oviedo, Spain

    Santiago Cal

  4. Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica-Universitat Pompeu-Fabra, E-08003, Barcelona, Spain

    Antonio García de Herreros

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  1. José Manuel González-Sancho
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Correspondence to Alberto Muñoz.

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González-Sancho, J., Aguilera, O., García, J. et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer. Oncogene 24, 1098–1103 (2005). https://doi.org/10.1038/sj.onc.1208303

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