Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice

Autor: G. Z. Wu, Huaxin Zhou, Austin J. Cooney, Xian Li, Junmei Zhou, Zi-Jian Lan, CheMyong Ko, M. S. Krause, Zhenmin Lei, Henry Bohler, S. D. Redding
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Aging
Chlorpropamide
endocrine system diseases
FOXO1
Androgen Excess
Biochemistry
0302 clinical medicine
Endocrinology
Testosterone
Phosphorylation
Promoter Regions
Genetic
biology
Forkhead Box Protein O1
Receptors
LH
female genital diseases and pregnancy complications
Theca
Theca Cells
Androgens
Female
Steroids
hormones
hormone substitutes
and hormone antagonists
Protein Binding
endocrine system
medicine.medical_specialty
medicine.drug_class
030209 endocrinology & metabolism
Protein Serine-Threonine Kinases
Models
Biological
03 medical and health sciences
Downregulation and upregulation
Internal medicine
medicine
Animals
PTEN
Molecular Biology
PI3K/AKT/mTOR pathway
Ovary
PTEN Phosphohydrolase
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Luteinizing Hormone
Androgen
Mice
Mutant Strains
Mice
Inbred C57BL
Fertility
030104 developmental biology
Gene Expression Regulation
biology.protein
Proto-Oncogene Proteins c-akt
Gene Deletion
Zdroj: Molecular and Cellular Endocrinology. 444:26-37
ISSN: 0303-7207
Popis: Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.
Databáze: OpenAIRE
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