User:Dimah Almahbub/sandbox

I planed to contribute in update this article FOXO1 with more information about the following:

1.The regulation of FOXO1 by phosphorylation in more details.

2.Function:

2.1.FOXO1 in Apoptosis

2.2.FOXO1 in Cell Cycle Regulation

3.Clinical significance

Here is a list of bibliography that I'm working on.

Gross, D. N., A. P. J. Van Den Heuvel, and M. J. Birnbaum. "The role of FoxO in the regulation of metabolism." Oncogene 27.16 (2008): 2320-2336.

Hedrick, Stephen M., et al. "FOXO transcription factors throughout T cell biology." Nature Reviews Immunology 12.9 (2012): 649-661.

Lu, Huarui, and Haojie Huang. "FOXO1: a potential target for human diseases." Current drug targets 12.9 (2011): 1235-1244.

Wang, Yu, Yanmin Zhou, and Dana T. Graves. "FOXO transcription factors: their clinical significance and regulation." BioMed Research International 2014 (2014).

Regulation

There are three processes, namely acetylation, phosphorylation, and ubiquitination that are responsible for regulation of the activity of forkhead box O1 (FOXO1).

Regulation of FOXO1 by Phosphorylation

Phosphorylation of the FOXO1 protein is a result of the activation of the PI3K /AKT pathway. Serum and glucocorticoid-inducible kinase SGK can also phosphorylate and inactivate FOXO1 transcription factor. FOXO1 translocate from the nucleus to cytoplasm and inactivate through phosphorylation at well-defined sites by AKT/SGK1 protein kinases. FOXO1 transcription factor can phosphorylate directly by AKT/SGK1 on three sites T24, S256 and S319. Additionally, FOXO1 loses its interactions with DNA when phosphorylated by AKT/SGK1 because S256, which is one of the three AKT/SGK sites, changes the DNA-binding domain charge from a positive charge to a negative charge.

Insulin signaling substrates 1 and 2 of the insulin-signaling cascade also regulate FOXO1 through phosphorylation by AKT. AKT, which is referred to as protein kinase B, phosphorylates FOXO1 and accumulates in the cytosol.

Casein kinase 1, a growth factor-activated protein kinase, also phosphorylates and potentiates FOXO1 and translocates FOXO1 to the cytoplasm. 

Function

FOXO1 in Apoptosis

FOXO1 may plays an important role in apoptosis because it phosphorylated and inhibited by AKT. When FOXO1 over expressed in human LNCaP prostate cancer cells, it caused apoptosis in these cancer cells. Also, It is detected that FOXO1 regulateTNF-related apoptosis-inducing ligand (TRAIL), which cause FOXO1-induced apoptosis in the human prostate cancer cell line LAPC4 when FOXO1 adenovirus-mediated overexpression was used. FOXO1 upregulate Fas ligand (FasL) transcriptionally that result in promotes apoptotic cell death. Additionally, FOXO1 trans-activate Bim protein, which a member of the Bcl-2 family that promotes apoptosis and plays a role in the intrinsic mitochondrial apoptotic pathway. Further, it was revealed that DNA damage-induced cell death in p53-deficient and p53-proficient cells reduced when human FOXO1 silenced by siRNA.

FOXO1 in Cell Cycle Regulation

FOXO1 activation plays a role in cell cycle progression regulation. The transcription and half- life of cyclin-dependent kinase inhibitor p27KIP1 rises when FOXO1 is active. A study detects that FOXO1 regulates the nuclear localization of p27KIP1 in porcine granulosa cells and impacts cell cycle progression. Furthermore, FOXO1-mediated cell cycle arrest is linked with cyclin D1 and cyclin D2 suppression in mammals. It was detected that human FOXO1 is linked with the cyclin D1 promoter using chromatin immunoprecipitation assays (ChIP assays). H215R is a human FOXO1 mutant, which cannot bind to the canonical FRE to induce expression of p27KIP1, repress cyclin D1 and cyclin D2 promoter activity and encourages cell cycle arrest at cyclin G1 (CCNG1). As a result of that, activation of FOXO1 prevents the cell-division cycle at cyclin G1 (CCNG1) out of one of two ways stimulating or suppressing gene transcription.

Clinical Significance

• In Gluconeogenesis, FOXO1 gene regulates the glucose levels due to the low output of hepatic glucose. In mice, it cuts fasting blood glucose levels by inhibiting formulation of the gluconeogenic genes.
• FOXO1 plays a role in the protection of cells from oxidative stress. It seems to promote cell death when oxidative stress is high in tissues that are involved in diabetic complications. In such situations, it has a destructive role instead of a protective role.
• FOXO1 helps in wound healing in mice through coordination of response of keratinocytes and functions in keratinocytes to bring down oxidative stress. 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.
• In the Innate Immune system, FOXO1 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.
• In Adaptive Immunity system, FOXO1 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.
• In Carcinogenesis, FOXO1 plays a 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 cells 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 or suppressing the Runt-domain containing Runx2 transcriptional activity.
• In insulin sensitivity and lipid metabolism, FOXO1 acts as a negative transcriptional modular for insulin sensing genes which lower sensitivity of the insulin. FOXO1 controls some of lipid metabolism in the diabetic liver.
• In cardiomyopathy, FOXO1 has a both positive and negative function in autophagy-linked to cardiomyopathy. It can cause autophagy and cut cardiomyocyte.
• In osteoblasts, recent evidence indicates that FOXO1 transcription factor has a fundamental role in skeletal homeostasis by upregulating antioxidant enzymes. Deletion of FOXO1 in osteoblast lead to decreased expression of antioxidants like glutathione.
• In diabetic complications, FOXO1 is linked to the healing of impaired fracture in patients with diabetes.