title: Unique roles of estrogen-dependent Pten control in epithelial cell homeostasis of mouse vagina.
abstract: Numerous studies support a role of phosphatase and tensin homolog deleted from chromosome 10 (Pten) as a tumor suppressor gene that controls epithelial cell homeostasis to prevent tumor formation. Mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing homeostasis of stratified squamous epithelia. We analyzed vaginal epithelium-specific Pten conditional knockout (CKO) mice to provide new insights into Pten/phosphoinositide-3-kinase (PI3K)/Akt function. The vaginal epithelium of ovariectomized (OVX) mice (control) was composed of 1-2 layers of cuboidal cells, whereas OVX CKO mice exhibited epithelial hyperplasia in the suprabasal cells with increased cell mass and mucin production. This is possibly due to misactivation of mammalian target of rapamycin and mitogen-activated protein kinase. Intriguingly, estrogen administration to OVX Pten CKO mice induced stratification and keratinized differentiation in the vaginal epithelium, as in estrogen-treated controls. We found that Pten is exclusively expressed in the suprabasal cells in the absence of estrogens, whereas estrogen administration induced Pten expression in the basal cells. This suggests that Pten acts to prevent excessive cell proliferation as in the case of other squamous tissues. Thus, Pten exhibits a dual role on the control of vaginal homeostasis, depending on whether estrogens are present or absent. Our results provide new insights into how Pten functions in tissue homeostasis.
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.affiliation: Section of Translational Research and Department of Gynecologic Oncology, Hyogo Cancer Center, Akashi, Hyogo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sudo
authors.affiliation: Department of Developmental Genetics and Laboratory Animal Center, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Wakayama, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Yamada
authors.affiliation: Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, The Graduate University for Advanced Studies, Okazaki, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iguchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000378:metabolism; D010052:Ovariectomy; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D014621:Vagina / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D009077:Mucins; D004958:Estradiol; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse