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The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing

 Soung Hoon Lee  ;  Mi Yeon Kim  ;  Hyun Yi Kim  ;  Young Mi Lee  ;  Heesu Kim  ;  Kyoung Ae Nam  ;  Mi Ryung Roh  ;  Do Sik Min  ;  Kee Yang Chung  ;  Kang Yell Choi 
 JOURNAL OF EXPERIMENTAL MEDICINE, Vol.212(7) : 1061-1080, 2015 
Journal Title
Issue Date
Actins/metabolism ; Adaptor Proteins, Signal Transducing/metabolism* ; Animals ; Blotting, Western ; Collagen/metabolism ; DNA Primers/genetics ; Dishevelled Proteins ; 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* ; beta Catenin/metabolism
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.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hee Su(김희수)
Roh, Mi Ryung(노미령) ORCID logo https://orcid.org/0000-0002-6285-2490
Chung, Kee Yang(정기양) ORCID logo https://orcid.org/0000-0003-3257-0297
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