Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 212, Issue 7, Pages 1061-1080Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141601
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Funding
- National Research Foundation (NRF)
- Ministry of Future Creation and Science (MFCS) of South Korea through the Mid-Career Researcher Program National Leading Research Lab [2012-010285]
- Translational Research Center for Protein Function Control [2009-0092955]
- Stem Cell Research Project [2010-0020235]
- BK21 PLUS program
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Wnt/beta-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/beta-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 beta-catenin, alpha-smooth muscle actin (alpha-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 beta-catenin and collagen production in vitro. Co-treatment of skin wounds with PTD-DBM and valproic acid (VPA), a glycogen synthase kinase 3 beta (GSK3 beta) inhibitor which activates the Wnt/beta-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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