The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death

• Published in: The EMBO journal Vol. 21; no. 5; pp. 966 - 975
• Main Authors: Grotewold, Lars, Rüther, Ulrich
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2002; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Animals; apoptosis; Apoptosis - genetics; Apoptosis - physiology; beta Catenin; Bmp; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins - antagonists & inhibitors; Bone Morphogenetic Proteins - pharmacology; Bone Morphogenetic Proteins - physiology; c-Jun; c-Jun gene; Carrier Proteins; Chick Embryo; Cytoskeletal Proteins - antagonists & inhibitors; Dickkopf-1 gene; Dkk-1; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Drug Implants; Enzyme Inhibitors - pharmacology; Extremities - embryology; Fibroblast Growth Factor 8; Fibroblast Growth Factors - pharmacology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Gene Expression Regulation, Developmental - radiation effects; Hedgehog Proteins; Intercellular Signaling Peptides and Proteins; Irradiation; limb development; Lymphoid Enhancer-Binding Factor 1; Mesoderm - metabolism; Mice; Mice, Knockout; Morphogenesis; Protein Biosynthesis; Proteins - genetics; Proteins - pharmacology; Proteins - physiology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-jun - physiology; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - physiology; RNA, Messenger - biosynthesis; s-catenin; Staurosporine - pharmacology; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - physiology; Transcription Factor AP-1 - physiology; Transcription Factors - biosynthesis; Transcription Factors - genetics; Ultraviolet radiation; Ultraviolet Rays; Vertebrates; Wings, Animal - embryology; Wnt protein; Wnt Proteins; Zebrafish Proteins
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/21.5.966

Dickkopf‐1 (Dkk‐1) has been shown to be a potent inhibitor of Wnt/β‐catenin signaling in a variety of assays and organisms. In this study, we show that expression of Dkk‐1 overlaps significantly with the sites of programmed cell death in normal as well as mutant vertebrate limb development, and identify several of its upstream regulators, one of which is Bmp‐4. Interestingly, Bmp‐4 only activates Dkk‐1 when it concomitantly induces apoptosis. Moreover, Dkk‐1 is heavily up‐regulated by UV irradiation and several other genotoxic stimuli. We further show that normal expression of Dkk‐1 is dependent on the Ap‐1 family member c‐Jun and that overexpression of Dkk‐1 enhances Bmp‐triggered apoptosis in the vertebrate limb. Taken together, our results provide evidence for an important role of Dkk‐1‐mediated inhibition of Wnt/β‐catenin signaling in response to different stress signals that all converge on the activation of c‐Jun in vivo.