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The Role of Foxo3 in Leydig Cells.

 Young Suk Choi  ;  Joo Eun Song  ;  Byung Soo Kong  ;  Jae Won Hong  ;  Silvia Novelli  ;  Eun Jig Lee 
 YONSEI MEDICAL JOURNAL, Vol.56(6) : 1590-1596, 2015 
Journal Title
Issue Date
Animals ; Cell Nucleus/metabolism ; Cellular Senescence/physiology* ; Cytoplasm/metabolism ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/metabolism* ; HEK293 Cells ; Humans ; Leydig Cells/drug effects* ; Leydig Cells/enzymology* ; Leydig Cells/metabolism ; Luteinizing Hormone/blood ; Male ; Mice ; Phosphatidylinositol 3-Kinases ; Phosphoproteins/metabolism ; Phosphorylation ; Signal Transduction/drug effects ; Testosterone/blood ; Testosterone/metabolism*
Foxo3 ; Leydig cell ; StAR ; testosterone
PURPOSE: Foxo3 in female reproduction has been reported to regulate proliferation of granulose cells that form follicles. There are no reports so far that discuss on the role of Foxo3 in males. This study was designed to outline the role of Foxo3 in the testes. MATERIALS AND METHODS: Testes from mice at birth to postpartum week (PPW) 5 were isolated and examined for the expression of Foxo3 using immunostaining. To elucidate role of Foxo3 in Leydig cells, R2C cells were treated with luteinizing hormone (LH) and the phosphorylation of Foxo3. Testosterone and steroidogenic acute regulatory (StAR) protein levels were measured after constitutive active [triple mutant (TM)] human FOXO3 adenovirus was transduced and StAR promoter assay was performed. RESULTS: Foxo3 expression in the testicles started from birth and lasted until PPW 3. After PPW 3, most Foxo3 expression occurred in the nuclei of Leydig cells; however, at PPW 5, Foxo3 was expressed in both the nucleus and cytoplasm. When R2C cells were treated with luteinizing hormone, Foxo3 phosphorylation levels by AKT increased. After blocking the PI3K pathway, LH-induced phosphorylated Foxo3 levels decreased, indicating that LH signaling regulates Foxo3 localization. When active FOXO3-TM adenovirus was introduced into a Leydig tumor cell line, the concentrations of testosterone and StAR protein decreased. When FOXO3 and a StAR promoter vector were co-transfected into HEK293 cells for a reporter assay, FOXO3 inhibited the StAR promoter. CONCLUSION: FOXO3 affects testosterone synthesis by inhibiting the formation of StAR protein. LH hormone, meanwhile, influences Foxo3 localization, mediating its function.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Choi, Young Suk(최영숙) ORCID logo https://orcid.org/0000-0003-4930-8455
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