title: FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress.
abstract: 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.
authors.affiliation: University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Ponugoti
authors.forename: Fanxing
authors.initials: F
authors.lastname: Xu
authors.forename: Chenying
authors.initials: C
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.forename: Sandra
authors.initials: S
authors.lastname: Pacios
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039422:Integrin alpha3 / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D039422:Integrin alpha3; D039641:Integrin beta Chains; D051785:Smad Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C072170:integrin beta6; D017364:Collagenases