Monica Rivera-Torres

1 University of Puerto Rico, Cayey, PR

Department of Biology

DYNAMIC REGULATION OF METABOLIC SYNDROMES BY POSTTRANSLATIONAL

MODIFICATIONS OF FORKHEAD TRANSCRIPTION FACTOR FOXO1

OBJECTIVES• Investigate the role of FOXO1 inactivation and activation:

• C. elegans WT and K/O Daf-16 to study fertilization processes

• Demonstrate Prostaglandin (PG) role on sperm guidance

Hypothalamic-Pituitary-Gonadal Axis

V.G. Thackray, 2013

WHAT IS FOXO1?

• Transcription factor

• Wide tissue expression, including gonadotrope cells

• Key transcription factor of metabolic homeostasis

• FOXO1 activity inhibited by activation of the PI3K/AKT pathway

• AKT directly phosphorylates FOXO1

Insulin

PI3K

PKB/AKT

FOXO1

ATP

ADP

SubstrateSubstrate

Kinase

Kinase phosphorylation of proteins

P

Insulin

PKB/AKT

FOXO1

ATP

ADP

SubstrateSubstrate

Kinase Phosphatase

Reversible Phosphorylation

P

Insulin Signaling Pathway

FOXO1P

Modified from Google images

FOXO1 subcellular localization is regulated by the PI3K/AKT pathway in LbT2 cells

InsulinVeh

FOXO1

DNA

HYPOTHESIS

Insulin induced reversible phosphorylation of FOXO1 regulates metabolic syndromes and diseases

• C. elegans model

• Representative sperm distribution images 1 hr after mating wild-type (WT) or mutant hermaphrodites to wild-type MitoTracker-labeled (MT) males. Yellow outline marks the spermatheca. Vulva is to the right.

INSULIN SIGNALING IS REQUIRED CELL NONAUTONOMOUSLY FOR SPERM GUIDANCE

Edmonds, 2010

• A previous study indicates that increased DAF-16(insulin receptor) activity in daf-2 mutants causes decreased levels of two prostaglandins (PGs). These PGs are important for sperm guidance and possibly ovulation.

• Infertility

INSULIN/FOXO SIGNALING REGULATES PROSTAGLANDIN SYNTHESIS

Edmonds, 2010

• Chronic liver disease in patients with hyperinsulinemia

• Inactivation of FOXO1 by the insulin induced phosphorylation increases Plasminogen Activator Inhibitor-1 gene expression. Excess of Plasminogen Activator Inhibitor-1 in patients with hyperinsulinemia is a risk factor for chronic liver disease.

INSULIN REGULATES PAI-1 EXPRESSION

Jung, 2009

SUMMARY• Question: What are the molecular mechanisms by which insulin signaling in FOXO1 is

related to metabolic syndromes?

• Posttranslational modifications in FOXO1 have been demonstrated to affect gene expression

• Studies in C. elegans have shown that insulin/FOXO1 pathway may lead to a type of Prostaglandin (PG) necessary for sperm guidance and therefore crucial for fertility.

• Insulin induced phosphorylation inhibits FOXO1 but activates some hormone secretions and gene expression (PAI-1). Excess of PAI-1 is a risk factor for patients with hyperinsulinemia and could develop chronic liver disease.

CONCLUSION

Reversible phosphorylation of FOX01s is the key point to many processes inside the cell. Understanding the functions of FOXO1s in their active and inactive states may shed the light to treatments for diseases like infertility, chronic liver disease, type 2 diabetes and other metabolic syndromes.

REFERENCES• Arriola, D J, Mayo, S. L., Skarra, D. V. 2012 FOXO1 Transcription Factor Inhibits

Luteinizing Hormone β Gene Expression in Pituitary Gonadotrope Cells. J. Biol. Chem. 287:33424-33435.

• Yun-A J, Kyeong-Min L, Mi-Kyung K, 2009, Fofkhead Transccription factor Fox01 inhibits insulin- and transformin growth factor-B-stimulated plasminogen activator inhibitor-1 expression, Biochem and Biophy R.C. 386 (2009) 757–761

• Edmonds J W, Prasain J K, Dorand D. 2010 Insulin/FOXO Signaling Regulates Ovarian Prostaglandins Critical for Reproduction. J. Dev. Cell. 19, 858-871.

• Nakae J, Oki M, Cao Y, The FoxO transcription factors and metabolic regulation, 2007, FEBS Letters 582 (2008) 54-67

• Kovacs K, Lengyel F, Wilhelm F, 2010, Involvement of FKHR (FOXO1) transcription factor in human uterus leiomyoma growth, J. Fert and Stert vol. 94, No. 4 1491-1495