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

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24 Citations (Scopus)

Abstract

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. Cotreatment 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.

Original languageEnglish
Pages (from-to)1061-1080
Number of pages20
JournalJournal of Experimental Medicine
Volume212
Issue number7
DOIs
Publication statusPublished - 2015 Jan 1

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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