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

EMBO J. 2002 Mar 1;21(5):966-75. doi: 10.1093/emboj/21.5.966.

Abstract

Dickkopf-1 (Dkk-1) has been shown to be a potent inhibitor of Wnt/beta-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/beta-catenin signaling in response to different stress signals that all converge on the activation of c-Jun in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / pharmacology
  • Bone Morphogenetic Proteins / physiology*
  • Carrier Proteins
  • Chick Embryo
  • Cytoskeletal Proteins / antagonists & inhibitors
  • 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
  • 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*
  • RNA, Messenger / biosynthesis
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / physiology
  • Staurosporine / pharmacology
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Ultraviolet Rays
  • Wings, Animal / embryology*
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • CTNNB1 protein, mouse
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Dkk1 protein, mouse
  • Drug Implants
  • Enzyme Inhibitors
  • Fgf8 protein, mouse
  • Hedgehog Proteins
  • Intercellular Signaling Peptides and Proteins
  • Lymphoid Enhancer-Binding Factor 1
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • bmp4 protein, zebrafish
  • dkk1b protein, zebrafish
  • noggin protein
  • Fibroblast Growth Factor 8
  • Fibroblast Growth Factors
  • Staurosporine