Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions

被引:210
作者
Adlanmerini, Marine [1 ]
Solinhac, Romain [1 ]
Abot, Anne [1 ]
Fabre, Aurelie [1 ]
Raymond-Letron, Isabelle [2 ]
Guihot, Anne-Laure [3 ]
Boudou, Frederic [1 ]
Sautier, Lucile [1 ,2 ]
Vessieres, Emilie [3 ]
Kim, Sung Hoon [4 ]
Liere, Philippe [5 ]
Fontaine, Coralie [1 ]
Krust, Andree [6 ]
Chambon, Pierre [6 ]
Katzenellenbogen, John A. [4 ]
Gourdy, Pierre [1 ]
Shaul, Philip W. [7 ]
Henrion, Daniel [3 ]
Arnal, Jean-Francois [1 ]
Lenfant, Francoise [1 ]
机构
[1] Univ Toulouse, Inst Natl Sante & Rech Med U1048, Inst Malad Metab & Cardiovasc, F-31432 Toulouse 4, France
[2] Univ Toulouse, Inst Natl Polytech, Ecole Natl Vet Toulouse, Inst Natl Sante & Rech Med,Unite Mixte Serv 006, F-31076 Toulouse, France
[3] Univ Angers, Inst Natl Sante & Rech Med U1083, Ctr Natl Rech Sci, Unite Mixte Rech 6214, F-49000 Angers, France
[4] Univ Illinois, Dept Chem, Champaign, IL 61820 USA
[5] Univ Paris 11, Inst Natl Sante & Rech Med, F-94270 Le Kremlin Bicetre, France
[6] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, Coll France, FR-67404 Illkirch Graffenstaden, France
[7] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75235 USA
基金
美国国家卫生研究院;
关键词
fertility; vascular effects; nongenomic effects; genomic actions; NITRIC-OXIDE SYNTHASE; ACTIVATION FUNCTION; LIGAND-BINDING; EXTRANUCLEAR; ESTRADIOL; BREAST; SIGNAL; INTEGRATION; UTERINE; CELLS;
D O I
10.1073/pnas.1322057111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Estrogen receptor alpha (ER alpha) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ER alpha is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ER alpha (C451A-ER alpha) to obtain membrane-specific loss of function of ER alpha. The abrogation of membrane localization of ER alpha in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ER alpha mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451AER alpha mice. A complementary mutant mouse lacking the transactivation function AF-2 of ER alpha (ER alpha-AF2 degrees) provided selective loss of function of nuclear ER alpha actions. In ER alpha-AF20, the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ER alpha-AF20, whereas in C451A-ER alpha it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.
引用
收藏
页码:E283 / E290
页数:8
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