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FOXO1, TGF-β regulation and wound healing.

Hameedaldeen A, Liu J, Batres A, Graves GS, Graves DT - Int J Mol Sci (2014)

Bottom Line: The induction of transcription factors during these processes is crucial for successful wound healing.The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing.In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

View Article: PubMed Central - PubMed

Affiliation: School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ahame@dental.upenn.edu.

ABSTRACT
Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

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(a) Oxidative stress increases in the inflammatory phase of wound healing. FOXO1 down-regulates oxidative stress by activating antioxidant genes and DNA repair enzymes. This facilitates keratinocyte migration and proliferation and decreases keratinocyte apoptosis, which improves wound healing; (b) FOXO1 stimulates TGF-β promoter activity resulting in the upregulation of TGF-β expression. Increased TGF-β stimulates expression of integrins and matrix metalloproteinases to improve wound healing through increased keratinocyte migration and decreased apoptosis.
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ijms-15-16257-f001: (a) Oxidative stress increases in the inflammatory phase of wound healing. FOXO1 down-regulates oxidative stress by activating antioxidant genes and DNA repair enzymes. This facilitates keratinocyte migration and proliferation and decreases keratinocyte apoptosis, which improves wound healing; (b) FOXO1 stimulates TGF-β promoter activity resulting in the upregulation of TGF-β expression. Increased TGF-β stimulates expression of integrins and matrix metalloproteinases to improve wound healing through increased keratinocyte migration and decreased apoptosis.

Mentions: FOXO1 activity is regulated by acetylation, phosphorylation and ubiquitination [16]. After activation, FOXO1 translocates to the nucleus and regulates transcription of other genes [16,31]. In the normal epidermis FOXO1 has a low level of expression and activation, both of which are significantly increased by wounding [31,32]. Wound healing increases the expression of genes with FOXO1 response elements [32]. One of the functions of FOXO1 in wound healing is protecting keratinocytes from oxidative stress by regulating antioxidant genes such as glutathione peroxidase 2 (GPX-2) [33]. FOXO1 also regulates DNA repair enzymes like GADD45, which further protects cells from ROS. FOXO1 deletion in keratinocytes increases oxidative stress by 38% [33]. High level of oxidative stress in turn impairs keratinocyte migration (Figure 1). In support of this, the negative effect of FOXO1 knockdown on keratinocyte migration in vitro can be rescued by treatment with an antioxidant [33]. FOXO1 deletion also leads to a 3.7-fold upregulation effect of oxidative stress on apoptosis. When cells are exposed to H2O2 FOXO1 deletion further increases the level of keratinocyte apoptosis induced by oxidative stress [33].


FOXO1, TGF-β regulation and wound healing.

Hameedaldeen A, Liu J, Batres A, Graves GS, Graves DT - Int J Mol Sci (2014)

(a) Oxidative stress increases in the inflammatory phase of wound healing. FOXO1 down-regulates oxidative stress by activating antioxidant genes and DNA repair enzymes. This facilitates keratinocyte migration and proliferation and decreases keratinocyte apoptosis, which improves wound healing; (b) FOXO1 stimulates TGF-β promoter activity resulting in the upregulation of TGF-β expression. Increased TGF-β stimulates expression of integrins and matrix metalloproteinases to improve wound healing through increased keratinocyte migration and decreased apoptosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4200873&req=5

ijms-15-16257-f001: (a) Oxidative stress increases in the inflammatory phase of wound healing. FOXO1 down-regulates oxidative stress by activating antioxidant genes and DNA repair enzymes. This facilitates keratinocyte migration and proliferation and decreases keratinocyte apoptosis, which improves wound healing; (b) FOXO1 stimulates TGF-β promoter activity resulting in the upregulation of TGF-β expression. Increased TGF-β stimulates expression of integrins and matrix metalloproteinases to improve wound healing through increased keratinocyte migration and decreased apoptosis.
Mentions: FOXO1 activity is regulated by acetylation, phosphorylation and ubiquitination [16]. After activation, FOXO1 translocates to the nucleus and regulates transcription of other genes [16,31]. In the normal epidermis FOXO1 has a low level of expression and activation, both of which are significantly increased by wounding [31,32]. Wound healing increases the expression of genes with FOXO1 response elements [32]. One of the functions of FOXO1 in wound healing is protecting keratinocytes from oxidative stress by regulating antioxidant genes such as glutathione peroxidase 2 (GPX-2) [33]. FOXO1 also regulates DNA repair enzymes like GADD45, which further protects cells from ROS. FOXO1 deletion in keratinocytes increases oxidative stress by 38% [33]. High level of oxidative stress in turn impairs keratinocyte migration (Figure 1). In support of this, the negative effect of FOXO1 knockdown on keratinocyte migration in vitro can be rescued by treatment with an antioxidant [33]. FOXO1 deletion also leads to a 3.7-fold upregulation effect of oxidative stress on apoptosis. When cells are exposed to H2O2 FOXO1 deletion further increases the level of keratinocyte apoptosis induced by oxidative stress [33].

Bottom Line: The induction of transcription factors during these processes is crucial for successful wound healing.The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing.In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

View Article: PubMed Central - PubMed

Affiliation: School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ahame@dental.upenn.edu.

ABSTRACT
Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

Show MeSH
Related in: MedlinePlus