FOXO transcription factors: their clinical significance and regulation

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.

Figure 1

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).

Figure 2

Explanation of FOXO1 clinical significance. FOXO1 is the best-studied member of FOXO subfamily. FOXO1 function has been investigated in the tissues and cells of various genetically modified mice of different disease models such as diabetic complications, cardiomyopathy, and carcinogenesis. FOXO1 has been shown to enhance or diminish the clinical events either based on animal studies or projection from in vitro studies.

Figure 3

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].