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FOXO transcription factors: their clinical significance and regulation.

Wang Y, Zhou Y, Graves DT - Biomed Res Int (2014)

Bottom Line: FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes.These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing.In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.

View Article: PubMed Central - PubMed

Affiliation: Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China ; Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.

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Mechanisms of FOXO1 in normal wound healing. The normal wound healing process is initiated by the integration of multiple intercellular signals (cytokines and chemokines) released by keratinocytes and other cells. FOXO1 is required for keratinocyte transition to a wound-healing phenotype. FOXO1 in vivo is needed for keratinocyte expression of transforming growth factor-β1 (TGF-β1) expression, induction of TGFβ1 downstream targets (integrin-α3 and -β6 and MMP-3 and -9), and migration. Migration (bold arrow) is particularly important in wound healing. FOXO1 is also needed to protect keratinocytes from oxidative stress, which contributes to keratinocyte migration and survival during normal wound healing. This is adapted from [19].
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fig3: Mechanisms of FOXO1 in normal wound healing. The normal wound healing process is initiated by the integration of multiple intercellular signals (cytokines and chemokines) released by keratinocytes and other cells. FOXO1 is required for keratinocyte transition to a wound-healing phenotype. FOXO1 in vivo is needed for keratinocyte expression of transforming growth factor-β1 (TGF-β1) expression, induction of TGFβ1 downstream targets (integrin-α3 and -β6 and MMP-3 and -9), and migration. Migration (bold arrow) is particularly important in wound healing. FOXO1 is also needed to protect keratinocytes from oxidative stress, which contributes to keratinocyte migration and survival during normal wound healing. This is adapted from [19].

Mentions: FOXO1 plays a positive role in wound healing in normal mice [19] (Figure 3). It coordinates the response of keratinocytes to wound healing through upregulation of TGF-β1 and its downstream targets, integrin-α3 and -β6, and MMP-3 and -9 which are needed for keratinocyte migration. FOXO1 also functions in keratinocytes to reduce oxidative stress that is necessary to maintain cell migration and prevent cell death in a TGFβ1 independent manner. However, in the diabetic wounds, FOXO1 has been linked to impaired wound healing. In diabetic wounds FOXO1 DNA binding activity and nuclear translocation are driven by TNF-α and associated with higher levels of apoptosis and reduced proliferation of fibroblasts [73, 74]. In vitro experiments suggest that FOXO1 may negatively affect fibroblasts through expression of proapoptotic factors [12].


FOXO transcription factors: their clinical significance and regulation.

Wang Y, Zhou Y, Graves DT - Biomed Res Int (2014)

Mechanisms of FOXO1 in normal wound healing. The normal wound healing process is initiated by the integration of multiple intercellular signals (cytokines and chemokines) released by keratinocytes and other cells. FOXO1 is required for keratinocyte transition to a wound-healing phenotype. FOXO1 in vivo is needed for keratinocyte expression of transforming growth factor-β1 (TGF-β1) expression, induction of TGFβ1 downstream targets (integrin-α3 and -β6 and MMP-3 and -9), and migration. Migration (bold arrow) is particularly important in wound healing. FOXO1 is also needed to protect keratinocytes from oxidative stress, which contributes to keratinocyte migration and survival during normal wound healing. This is adapted from [19].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016844&req=5

fig3: Mechanisms of FOXO1 in normal wound healing. The normal wound healing process is initiated by the integration of multiple intercellular signals (cytokines and chemokines) released by keratinocytes and other cells. FOXO1 is required for keratinocyte transition to a wound-healing phenotype. FOXO1 in vivo is needed for keratinocyte expression of transforming growth factor-β1 (TGF-β1) expression, induction of TGFβ1 downstream targets (integrin-α3 and -β6 and MMP-3 and -9), and migration. Migration (bold arrow) is particularly important in wound healing. FOXO1 is also needed to protect keratinocytes from oxidative stress, which contributes to keratinocyte migration and survival during normal wound healing. This is adapted from [19].
Mentions: FOXO1 plays a positive role in wound healing in normal mice [19] (Figure 3). It coordinates the response of keratinocytes to wound healing through upregulation of TGF-β1 and its downstream targets, integrin-α3 and -β6, and MMP-3 and -9 which are needed for keratinocyte migration. FOXO1 also functions in keratinocytes to reduce oxidative stress that is necessary to maintain cell migration and prevent cell death in a TGFβ1 independent manner. However, in the diabetic wounds, FOXO1 has been linked to impaired wound healing. In diabetic wounds FOXO1 DNA binding activity and nuclear translocation are driven by TNF-α and associated with higher levels of apoptosis and reduced proliferation of fibroblasts [73, 74]. In vitro experiments suggest that FOXO1 may negatively affect fibroblasts through expression of proapoptotic factors [12].

Bottom Line: FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes.These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing.In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.

View Article: PubMed Central - PubMed

Affiliation: Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China ; Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.

Show MeSH
Related in: MedlinePlus