The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing

Wnt/β-catenin signaling plays important roles in cutaneous wound healing and dermal fibrosis. However, its regulatory mechanism has not been fully elucidated, and a commercially available wound-healing agent targeting this pathway is desirable but currently unavailable. We found that CXXC-type zinc...

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Bibliographic Details
Published in:The Journal of experimental medicine 2015-06, Vol.212 (7), p.1061-1080
Main Authors: Lee, Soung-Hoon, Kim, Mi-Yeon, Kim, Hyun-Yi, Lee, Young-Mi, Kim, Heesu, Nam, Kyoung Ae, Roh, Mi Ryung, Min, Do Sik, Chung, Kee Yang, Choi, Kang-Yell
Format: Article
Language:English
Subjects:
Actins - metabolism
Adaptor Proteins, Signal Transducing - metabolism
Animals
beta Catenin - metabolism
Blotting, Western
Collagen - metabolism
Dishevelled Proteins
DNA Primers - genetics
Fibroblasts - metabolism
Galactosides
Histological Techniques
Humans
Immunohistochemistry
Immunoprecipitation
Indoles
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Keratin-14 - metabolism
Keratinocytes - metabolism
Mice
Mice, Knockout
Phosphoproteins - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Skin Physiological Phenomena
Wnt Signaling Pathway - physiology
Wound Healing - physiology
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Summary:Wnt/β-catenin signaling plays important roles in cutaneous wound healing and dermal fibrosis. However, its regulatory mechanism has not been fully elucidated, and a commercially available wound-healing agent targeting this pathway is desirable but currently unavailable. We found that CXXC-type zinc finger protein 5 (CXXC5) serves as a negative feedback regulator of the Wnt/β-catenin pathway by interacting with the Dishevelled (Dvl) protein. In humans, CXXC5 protein levels were reduced in epidermal keratinocytes and dermal fibroblasts of acute wounds. A differential regulation of β-catenin, α-smooth muscle actin (α-SMA), and collagen I by overexpression and silencing of CXXC5 in vitro indicated a critical role for this factor in myofibroblast differentiation and collagen production. In addition, CXXC5(-/-) mice exhibited accelerated cutaneous wound healing, as well as enhanced keratin 14 and collagen synthesis. Protein transduction domain (PTD)-Dvl-binding motif (DBM), a competitor peptide blocking CXXC5-Dvl interactions, disrupted this negative feedback loop and activated β-catenin and collagen production in vitro. Co-treatment of skin wounds with PTD-DBM and valproic acid (VPA), a glycogen synthase kinase 3β (GSK3β) inhibitor which activates the Wnt/β-catenin pathway, synergistically accelerated cutaneous wound healing in mice. Together, these data suggest that CXXC5 would represent a potential target for future therapies aimed at improving wound healing.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20141601