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The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer.
Oncogene. 2005 Feb 03; 24(6):1098-103.O

Abstract

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 Ca(2+) 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.

Authors+Show Affiliations

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, E-28029 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15592505

Citation

González-Sancho, José Manuel, et al. "The Wnt Antagonist DICKKOPF-1 Gene Is a Downstream Target of beta-catenin/TCF and Is Downregulated in Human Colon Cancer." Oncogene, vol. 24, no. 6, 2005, pp. 1098-103.
González-Sancho JM, Aguilera O, García JM, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24(6):1098-103.
González-Sancho, J. M., Aguilera, O., García, J. M., Pendás-Franco, N., Peña, C., Cal, S., García de Herreros, A., Bonilla, F., & Muñoz, A. (2005). The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene, 24(6), 1098-103.
González-Sancho JM, et al. The Wnt Antagonist DICKKOPF-1 Gene Is a Downstream Target of beta-catenin/TCF and Is Downregulated in Human Colon Cancer. Oncogene. 2005 Feb 3;24(6):1098-103. PubMed PMID: 15592505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. AU - González-Sancho,José Manuel, AU - Aguilera,Oscar, AU - García,José Miguel, AU - Pendás-Franco,Natalia, AU - Peña,Cristina, AU - Cal,Santiago, AU - García de Herreros,Antonio, AU - Bonilla,Félix, AU - Muñoz,Alberto, PY - 2004/12/14/pubmed PY - 2005/3/3/medline PY - 2004/12/14/entrez SP - 1098 EP - 103 JF - Oncogene JO - Oncogene VL - 24 IS - 6 N2 - 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 Ca(2+) 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/15592505/The_Wnt_antagonist_DICKKOPF_1_gene_is_a_downstream_target_of_beta_catenin/TCF_and_is_downregulated_in_human_colon_cancer_ L2 - https://doi.org/10.1038/sj.onc.1208303 DB - PRIME DP - Unbound Medicine ER -