FOXO1 Promotes Wound Healing Through the Up-Regulation of TGF-Î21 and Prevention of Oxidative Stress

Keratinocyte mobilization is a critical aspect of wound re-epithelialization, but the mechanisms that control its precise regulation remain poorly understood. We set out to test the hypothesis that forkhead box O1 (FOXO1) has a negative effect on healing because of its capacity to inhibit proliferation and promote apoptosis. Contrary to expectations, FOXO1 is required for keratinocyte transition to a wound-healing phenotype that involves increased migration and up-regulation of transforming growth factor β1 (TGF-β1) and its downstream targets, integrin-α3 and -β6 and MMP-3 and -9. Furthermore, we show that FOXO1 functions in keratinocytes to reduce oxidative stress, which is necessary to maintain cell migration and prevent cell death in a TGF-β1–independent manner. Thus, our studies identify a novel function for FOXO1 in coordinating the response of keratinocytes to wounding through up-regulation of TGF-β1 and other factors needed for keratinocyte migration and protection against oxidative stress, which together promote migration and decrease apoptosis. Disciplines Amino Acids, Peptides, and Proteins | Medical Genetics Comments Supplemental materials are included at the end of the PDF. Author(s) Bhaskar Ponugoti, Fanxing Xu, Chenying Zhang, Chen Tian, Sandra Pacios, and Dana T. Graves This journal article is available at ScholarlyCommons: http://repository.upenn.edu/dental_papers/23