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FOXO1 differentially regulates both normal and diabetic wound healing.
- Source :
-
The Journal of cell biology [J Cell Biol] 2015 Apr 27; Vol. 209 (2), pp. 289-303. - Publication Year :
- 2015
-
Abstract
- Healing is delayed in diabetic wounds. We previously demonstrated that lineage-specific Foxo1 deletion in keratinocytes interfered with normal wound healing and keratinocyte migration. Surprisingly, the same deletion of Foxo1 in diabetic wounds had the opposite effect, significantly improving the healing response. In normal glucose media, forkhead box O1 (FOXO1) enhanced keratinocyte migration through up-regulating TGFβ1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGFβ1 promoter or stimulate TGFβ1 transcription. Instead, in high glucose, FOXO1 enhanced expression of serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), and chemokine (C-C motif) ligand 20 (CCL20). The impact of high glucose on keratinocyte migration was rescued by silencing FOXO1, by reducing SERPINB2 or CCL20, or by insulin treatment. In addition, an advanced glycation end product and tumor necrosis factor had a similar regulatory effect on FOXO1 and its downstream targets and inhibited keratinocyte migration in a FOXO1-dependent manner. Thus, FOXO1 expression can positively or negatively modulate keratinocyte migration and wound healing by its differential effect on downstream targets modulated by factors present in diabetic healing.<br /> (© 2015 Zhang et al.)
- Subjects :
- Animals
Apoptosis
Blotting, Western
Cell Movement
Cells, Cultured
Chemokine CCL20 genetics
Chromatin Immunoprecipitation
Diabetes Mellitus, Experimental drug therapy
Female
Fluorescent Antibody Technique
Forkhead Box Protein O1
Humans
Hypoglycemic Agents pharmacology
Keratinocytes cytology
Keratinocytes metabolism
Male
Mice
Mice, Knockout
Promoter Regions, Genetic genetics
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Serpins genetics
Transcriptional Activation
Transforming Growth Factor beta1 metabolism
Chemokine CCL20 metabolism
Diabetes Mellitus, Experimental physiopathology
Forkhead Transcription Factors physiology
Insulin pharmacology
Serpins metabolism
Wound Healing physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8140
- Volume :
- 209
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 25918228
- Full Text :
- https://doi.org/10.1083/jcb.201409032