| First Author | Lee SH | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 7 | Pages | 1061-80 |
| PubMed ID | 26056233 | Mgi Jnum | J:226362 |
| Mgi Id | MGI:5697131 | Doi | 10.1084/jem.20141601 |
| Citation | Lee SH, et al. (2015) The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing. J Exp Med 212(7):1061-80 |
| abstractText | 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 3beta (GSK3beta) 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. |
