title: Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function.
abstract: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Szwarc
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, College of Human Medicine, Grand Rapids, Michigan, United States of America.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: San-Pin
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D051958:Nuclear Receptor Coactivator 2