Regulation of FOXO1 by Phosphorylation

The acetylation, phosphorylation, and ubiquitination mechanisms are in charge of controlling the activity of forkhead box O1 (FOXO1). The transcription of other genes is controlled once FOXO1 is translocated to the nucleus and activated. In the normal epidermis, expression and activation both markedly rise with injury. Phosphatidylinositide activates the downstream insulin signaling protein kinase Ak strain transforming (Akt), also known as protein kinase, by phosphorylating the insulin receptor substrates -1 and -2.
One of Akt's substrates, FOXO1, is inactivated by Akt through phosphorylation (Hameedaldeen, Liu and Batres 16262). Phosphorylation of the FOXO1 protein is a result of the activation of the P13/Akt pathway. The process occurs in three stages, that is, threonine 24, serine 25 and serine 319 which lead to the nuclear exclusion of FOXO1 and suppression of its function (Barbato, Aquilano and Ciriolo 1555). Through phosphorylation FOXO1 transcription, the DAF-2 insulin receptor controls the DAF-16 activity.

FOXO1 in Carcinogenesis

FOXO1 plays role of a tumor suppressor and its inactivation has been documented in many kinds of human cancer. It suppresses survival of tumor cells by inducing apoptosis in prostate cancer and glioma cells by upregulating the proapoptotic factors. Increased activation of FOXO1 may inhibit the metastasis of the prostate cancer cells to other organs by suppressing the migration and invasion by suppressing the Runt-domain containing Runx2 transcriptional activity. (Wang, Zhou and Graves 6).

In some situations, FOXO1 can induce the expression of genes that impart resistance to chemotherapy. Unlike deletion of a single FOXO1, deletion of several FOXOs creates a more severe susceptibility to thymic lymphomas and hemangiomas. Vivo experiments indicate that lymphomas show an enrichment of the null elleles for the three FOXO genes followed by a marked FOXO decrease. Total loss of the FOXO gene role in the thymocytes predisposes to lymphogenesis by mechanisms that promote cellular proliferation and survival.

FOXO1 in Diabetes

Diabetes causes a range of complications including stroke, kidney failure, blindness, heart disease and delayed wound healing. Among the factors that may contribute to impaired healing in diabetics like increased blood glucose which result in the greater formation of advanced glycation end products (AGEs). Wound healing is a very complicated biological process and studies have indicated that FOXO1 transcription factor helps in orchestrating events that enhance the healing process in keratinocytes. Localization of FOXO1 nuclear increased four times in wound-healing keratinocytes. It encourages the migration of the keratinocytes through upregulating the growth factor (Xiao and Graves 1025).

FOXO1 in Skeletal Muscle

According to the recent evidence, FOXO factors help in skeletal muscle homeostasis through upregulation of the antioxidant enzymes and also promoting differentiation which is fundamental in bone formation (Wang, Zhou and Graves 7).



FOXO1 in Immune System

FOXO1 enhances formulation of the receptors that regulate the T cell trafficking to the lymphoid organ tissues and regulates the T cells tolerance and naive T cell homeostasis by initiation of IL-7R expression (Wang, Zhou and Graves 7).

Clinical Significance of FOXO1 as a Therapeutic Target Protein

According to Wang, Zhou and Graves (4 – 7), the importance of FOXO1 as therapeutic target protein are as follows;

Gluconeogenesis

FOXO1 gene regulates the glucose levels due to low output of hepatic glucose. In mice, it cuts fasting blood glucose levels by inhibiting formulation of the gluconeogenic genes.

Oxidative Stress

It plays a role in protection of cells from oxidative stress. However, it seems to promote cell death when oxidative stress is too much like in tissues that are involved in diabetic complications. In such situations, it has a destructive role instead of a protective role.

Wound Healing

It helps in wound healing in mice through coordination of response of keratinocytes and functions in keratinocytes to bring down oxidative stress.

Innate Immune Response

It has been proved that it enhances inflammation through increasing formulation of several proinflammatory genes. It mediates formulation of proinflammatory cytokines in response to high glucose levels, TNF and LPS stimulation.

Adaptive Immunity

It regulates the return of peripheral B cells by upregulation of L-section and controls class-switch recombination of peripheral B cells and in T cells it enhances survival of CD8 memory.

Carcinogenesis

Activation of FOXO1 has been proven to inhibit the survival of tumor cells. It suppresses tumor and its inactivation has been shown in many types of human cancer.

Insulin Sensitivity and Lipid Metabolism

It acts as a negative transcriptional modular for insulin sensing genes which lowers sensitivity of the insulin. FOXO1 controls some of the aspects of lipid metabolism in the diabetic liver.

Cardiomyopathy

It has a both positive and negative function in autophagy linked to cardiomyopathy. It can cause autophagy and cut cardiomyocyte.

Osteoblasts

Recent evidence indicates that FOXO factors have a fundamental role in skeletal homeostasis by upregulating antioxidant enzymes. Deletion of FOXO1 in osteoblast lead to decreased expression of antioxidants like glutathione.

Diabetic Complications

It is linked to the healing of impaired fracture in persons with diabetes.

Works Cited

Barbato, Daniele Lettieri, Katia Aquilano and Maria R Ciriolo. "FoxO1 at the Nexus Between Fat Catabolism and Longevity Pathways." Elsevier (2014): 1555 - 1560. Print.

Hameedaldeen, Alhassan, et al. "FOXO1, TGF-B Regulation and Wound Healing." International Journal of Molecular Sciences (2014): 16258 - 16265. Print.

Wang, Yu, Yanmin Zhou and Dana T Graves. "FOXO Transcription Factors: Their Clinical Significance and Regulation." BioMed Research International (2014): 1 - 13. Print.

Xiao, E and D T Graves. "Impact of Diabetes on the Protective Role of FOXO1 in Wound Healing." Journal of Dental Research (2015): 1025 - 1026. Print.