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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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Related in: MedlinePlus

Regulatory motifs of FOXO1 (655aa), FOXO3 (673aa), FOXO4 (505aa), and FOXO6 (492aa). The functional domains are indicated: forkhead domain (teal), nuclear localization (brown/gray), nuclear export (red), and transactivation (pink).
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fig1: Regulatory motifs of FOXO1 (655aa), FOXO3 (673aa), FOXO4 (505aa), and FOXO6 (492aa). The functional domains are indicated: forkhead domain (teal), nuclear localization (brown/gray), nuclear export (red), and transactivation (pink).

Mentions: FOXO transcriptional activity is regulated by a complex array of posttranslational modifications. These modifications can be either activating or inactivating. They alter nuclear import and export steps, modify the DNA binding affinity, and alter the pattern of transcriptional activity for specific target. FOXOs share significant sequence homology and possess four distinct functional motifs which include a forkhead, nuclear localization, nuclear export, and transactivation domains (Figure 1). These domains are highly conserved. FOXO1 and FOXO3 proteins are larger (greater than 650 amino acids) than FOXO4 and FOXO6, which are closer to 500 amino acids. FOXOs recognize two response elements: Daf-16 family member binding element (5′-GTAAA(T/C)AA) and insulin-responsive element (5′-(C/A)(A/C)AAA(C/T)AA). The core DNA sequence 5′-(A/C)AA(C/T)A-3′ is recognized by all FOX-family members. Although FOXOs recognize both Daf-16 family member binding element and the insulin response element, they have a higher affinity for the former [8]. The transport of FOXO proteins through the nuclear pore is dependent on active-transport mechanisms. The presence of a nuclear localization sequence is a prerequisite for maintaining proteins in the nucleus, whereas a nuclear export sequence maintains proteins in the cytosol. FOXO proteins have both a nuclear localization sequence and a nuclear export sequence within the C-terminal DNA binding domain. Kinases and interactions with other proteins modulate the effectiveness of these nuclear localization sequences and nuclear export sequences, which forms the basis of FOXO shuttling in and out of the nuclear compartment. The cytoplasmic sequestration of FOXO proteins is mediated by a combination of binding partners and changes in the properties of FOXO. The chaperone protein 14-3-3 binds to FOXO factors in the nucleus and allows their active export [9]. It also blocks the nuclear localization signal to prevent FOXO re-entry into the nucleus [10].


FOXO transcription factors: their clinical significance and regulation.

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

Regulatory motifs of FOXO1 (655aa), FOXO3 (673aa), FOXO4 (505aa), and FOXO6 (492aa). The functional domains are indicated: forkhead domain (teal), nuclear localization (brown/gray), nuclear export (red), and transactivation (pink).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Regulatory motifs of FOXO1 (655aa), FOXO3 (673aa), FOXO4 (505aa), and FOXO6 (492aa). The functional domains are indicated: forkhead domain (teal), nuclear localization (brown/gray), nuclear export (red), and transactivation (pink).
Mentions: FOXO transcriptional activity is regulated by a complex array of posttranslational modifications. These modifications can be either activating or inactivating. They alter nuclear import and export steps, modify the DNA binding affinity, and alter the pattern of transcriptional activity for specific target. FOXOs share significant sequence homology and possess four distinct functional motifs which include a forkhead, nuclear localization, nuclear export, and transactivation domains (Figure 1). These domains are highly conserved. FOXO1 and FOXO3 proteins are larger (greater than 650 amino acids) than FOXO4 and FOXO6, which are closer to 500 amino acids. FOXOs recognize two response elements: Daf-16 family member binding element (5′-GTAAA(T/C)AA) and insulin-responsive element (5′-(C/A)(A/C)AAA(C/T)AA). The core DNA sequence 5′-(A/C)AA(C/T)A-3′ is recognized by all FOX-family members. Although FOXOs recognize both Daf-16 family member binding element and the insulin response element, they have a higher affinity for the former [8]. The transport of FOXO proteins through the nuclear pore is dependent on active-transport mechanisms. The presence of a nuclear localization sequence is a prerequisite for maintaining proteins in the nucleus, whereas a nuclear export sequence maintains proteins in the cytosol. FOXO proteins have both a nuclear localization sequence and a nuclear export sequence within the C-terminal DNA binding domain. Kinases and interactions with other proteins modulate the effectiveness of these nuclear localization sequences and nuclear export sequences, which forms the basis of FOXO shuttling in and out of the nuclear compartment. The cytoplasmic sequestration of FOXO proteins is mediated by a combination of binding partners and changes in the properties of FOXO. The chaperone protein 14-3-3 binds to FOXO factors in the nucleus and allows their active export [9]. It also blocks the nuclear localization signal to prevent FOXO re-entry into the nucleus [10].

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