title: The AF-1 activation function of estrogen receptor α is necessary and sufficient for uterine epithelial cell proliferation in vivo.
abstract: Estrogen receptor-α (ERα) regulates gene transcription through the 2 activation functions (AFs) AF-1 and AF-2. The crucial role of ERαAF-2 was previously demonstrated for endometrial proliferative action of 17β-estradiol (E2). Here, we investigated the role of ERαAF-1 in the regulation of gene transcription and cell proliferation in the uterus. We show that acute treatment with E2 or tamoxifen, which selectively activates ERαAF-1, similarly regulate the expression of a uterine set of estrogen-dependent genes as well as epithelial cell proliferation in the uterus of wild-type mice. These effects were abrogated in mice lacking ERαAF-1 (ERαAF-1(0)). Four weeks of E2 treatment led to uterine hypertrophy and sustained luminal epithelial and stromal cell proliferation in wild-type mice, but not in ERαAF-1(0) mice. However, ERαAF-1(0) mice still presented a moderate uterine hypertrophy essentially due to a stromal edema, potentially due to the persistence of Vegf-a induction. Epithelial apoptosis is largely decreased in these ERαAF-1(0) uteri, and response to progesterone is also altered. Finally, E2-induced proliferation of an ERα-positive epithelial cancer cell line was also inhibited by overexpression of an inducible ERα isoform lacking AF-1. Altogether, these data highlight the crucial role of ERαAF-1 in the E2-induced proliferative response in vitro and in vivo. Because ERαAF-1 was previously reported to be dispensable for several E2 extrareproductive protective effects, an optimal ERα modulation could be obtained using molecules activating ERα with a minimal ERαAF-1 action.
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Abot
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.forename: Marine
authors.initials: M
authors.lastname: Adlanmerini
authors.forename: Melissa
authors.initials: M
authors.lastname: Buscato
authors.forename: Christiane
authors.initials: C
authors.lastname: Otto
authors.forename: Hortense
authors.initials: H
authors.lastname: Bergès
authors.forename: Henrik
authors.initials: H
authors.lastname: Laurell
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014599:Uterus / Q000166:cytology / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D013629:Tamoxifen; D004958:Estradiol