title: A role for site-specific phosphorylation of mouse progesterone receptor at serine 191 in vivo.
abstract: Progesterone receptors (PRs) are phosphorylated on multiple sites, and a variety of roles for phosphorylation have been suggested by cell-based studies. Previous studies using PR-null mice have shown that PR plays an important role in female fertility, regulation of uterine growth, the uterine decidualization response, and proliferation as well as ductal side-branching and alveologenesis in the mammary gland. To study the role of PR phosphorylation in vivo, a mouse was engineered with homozygous replacement of PR with a PR serine-to-alanine mutation at amino acid 191. No overt phenotypes were observed in the mammary glands or uteri of PR S191A treated with progesterone (P4). In contrast, although PR S191A mice were fertile, litters were 19% smaller than wild type and the estrous cycle was lengthened slightly. Moreover, P4-dependent gene regulation in primary mammary epithelial cells (MECs) was altered in a gene-selective manner. MECs derived from wild type and PR S191A mice were grown in a three-dimensional culture. Both formed acinar structures that were morphologically similar, and proliferation was stimulated equally by P4. However, P4 induction of receptor activator of nuclear factor-κB ligand and calcitonin was selectively reduced in S191A cultures. These differences were confirmed in freshly isolated MECs. Chromatin immunoprecipitation analysis showed that the binding of S191A PR to some of the receptor activator of nuclear factor-κB ligand enhancers and a calcitonin enhancer was substantially reduced. Thus, the elimination of a single phosphorylation site is sufficient to modulate PR activity in vivo. PR contains many phosphorylation sites, and the coordinate regulation of multiple sites is a potential mechanism for selective modulation of PR function.
authors.affiliation: Departments of Molecular and Cellular Biology (S.L.G., R.D.W., A.E.O., H.L.F., R.F.-V., J.-S.K., J.M.R., J.-W.J., F.J.D., J.P.L., D.P.E., N.L.W.) and Pathology and Immunology (D.P.E.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Grimm
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ward
authors.forename: Alison E
authors.initials: AE
authors.lastname: Obr
authors.forename: Heather L
authors.initials: HL
authors.lastname: Franco
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernandez-Valdivia
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Justin M
authors.initials: JM
authors.lastname: Roberts
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
mesh_terms: D000818:Animals; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D010766:Phosphorylation; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; D012694:Serine