The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ER alpha through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissue-selective function of TAM, we generated an AF-2-mutated ER alpha knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ER alpha-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ER alpha protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM- and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM- or E2-treated WT mice. The functionality of the mutant ER alpha in the pituitary appears to be different from that in the uterus, indicating that ER alpha uses AF-1 differently in the uterus and the pituitary for TAM action.
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Borjesson, A. E.
;
Windahl, S. H.
论文数: 0引用数: 0
h-index: 0
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Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Windahl, S. H.
;
Lagerquist, M. K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Lagerquist, M. K.
;
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机构:
Engdahl, C.
;
Frenkel, B.
论文数: 0引用数: 0
h-index: 0
机构:
Univ So Calif, Keck Sch Med, Dept Orthopaed Surg, Los Angeles, CA 90007 USA
Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90007 USAUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Frenkel, B.
;
Moverare-Skrtic, S.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Moverare-Skrtic, S.
;
Sjogren, K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Sjogren, K.
;
Kindblom, J. M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Kindblom, J. M.
;
Stubelius, A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Stubelius, A.
;
Islander, U.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Islander, U.
;
Antal, M. C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Antal, M. C.
;
Krust, A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Krust, A.
;
Chambon, P.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
DANIELIAN, PS
;
WHITE, R
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
WHITE, R
;
HOARE, SA
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
HOARE, SA
;
FAWELL, SE
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
FAWELL, SE
;
PARKER, MG
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Borjesson, A. E.
;
Windahl, S. H.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Windahl, S. H.
;
Lagerquist, M. K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Lagerquist, M. K.
;
论文数: 引用数:
h-index:
机构:
Engdahl, C.
;
Frenkel, B.
论文数: 0引用数: 0
h-index: 0
机构:
Univ So Calif, Keck Sch Med, Dept Orthopaed Surg, Los Angeles, CA 90007 USA
Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90007 USAUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Frenkel, B.
;
Moverare-Skrtic, S.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Moverare-Skrtic, S.
;
Sjogren, K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Sjogren, K.
;
Kindblom, J. M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Kindblom, J. M.
;
Stubelius, A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Stubelius, A.
;
Islander, U.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, SwedenUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Islander, U.
;
Antal, M. C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Antal, M. C.
;
Krust, A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
Krust, A.
;
Chambon, P.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Strasbourg, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, FranceUniv Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
DANIELIAN, PS
;
WHITE, R
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
WHITE, R
;
HOARE, SA
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
HOARE, SA
;
FAWELL, SE
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND
FAWELL, SE
;
PARKER, MG
论文数: 0引用数: 0
h-index: 0
机构:
IMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLANDIMPERIAL CANC RES FUND, MOLEC ENDOCRINOL LAB, 44 LINCOLNS INN FIELDS, LONDON WC2A 3PX, ENGLAND