Dissecting the basis of nongenomic activation of endothelial nitric oxide synthase by estradiol:: Role of ERα domains with known nuclear functions

被引:60
作者
Chambliss, KL [1 ]
Simon, L [1 ]
Yuhanna, IS [1 ]
Mineo, C [1 ]
Shaul, PW [1 ]
机构
[1] Univ Texas, SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA
关键词
D O I
10.1210/me.2004-0008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Estradiol stimulates endothelial nitric oxide synthase (eNOS) via the activation of plasma membrane (PM)-associated estrogen receptor (ER) alpha. The process requires Src and erk signaling and eNOS phosphorylation by phosphoinositide 3-kinase (PI3 kinase)-Akt kinase, with Src and PI3 kinase associating with ERalpha upon ligand activation. To delineate the basis of nongenomic eNOS stimulation, the potential roles of ERalpha domains necessary for classical nuclear function were investigated in COS-7 cells. In cross-linking studies, estradiol-17beta (E-2) caused PM-associated ERalpha to form dimers. However, eNOS activation by E-2 was unaltered for a dimerization-deficient mutant ERalpha (ERalphaL511R). In contrast, ERalpha mutants lacking the nuclear localization signals (NLS), NLS2,3 (ERalphaDelta250-274) or the DNA binding domain (ERalphaDelta185-251), which targeted normally to PM and caveolae/rafts, were incapable of activating eNOS. The loss of NLS2/NLS3 prevented Src and erk activation, and it altered ligand-induced PI3 kinase-ERalpha interaction and prevented eNOS phosphorylation. Loss of the DNA binding domain did not change E-2 activation of Src or erk, but ligand-induced PI3 kinase-ERalpha binding and eNOS phosphorylation did not occur. Thus, dimerization is not required for ERalpha coupling to eNOS; however, NLS2/NLS3 plays a role in Src activation, and the DNA binding region is involved in the dynamic interaction between ERalpha and PI3 kinase.
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收藏
页码:277 / 289
页数:13
相关论文
共 44 条
  • [1] Selective interaction of hsp90 with an estrogen receptor ligand-binding domain containing a point mutation
    Aumais, JP
    Lee, HS
    Lin, R
    White, JH
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (18) : 12229 - 12235
  • [2] Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc
    Barletta, F
    Wong, CW
    McNally, C
    Komm, BS
    Katzenellenbogen, B
    Cheskis, BJ
    [J]. MOLECULAR ENDOCRINOLOGY, 2004, 18 (05) : 1096 - 1108
  • [3] Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation
    Blair, A
    Shaul, PW
    Yuhanna, IS
    Conrad, PA
    Smart, EJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (45) : 32512 - 32519
  • [4] BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
  • [5] Estrogen receptor α and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae
    Chambliss, KL
    Yuhanna, IS
    Mineo, C
    Liu, PS
    German, Z
    Sherman, TS
    Mendelsohn, ME
    Anderson, RGW
    Shaul, PW
    [J]. CIRCULATION RESEARCH, 2000, 87 (11) : E44 - E52
  • [6] Estrogen modulation of endothelial nitric oxide synthase
    Chambliss, KL
    Shaul, PW
    [J]. ENDOCRINE REVIEWS, 2002, 23 (05) : 665 - 686
  • [7] ERβ has nongenomic action in caveolae
    Chambliss, KL
    Yuhanna, IS
    Anderson, RGW
    Mendelsohn, ME
    Shaul, PW
    [J]. MOLECULAR ENDOCRINOLOGY, 2002, 16 (05) : 938 - 946
  • [8] THE ROLE OF ESTROGEN RESPONSE ELEMENTS IN EXPRESSION OF THE XENOPUS-LAEVIS VITELLOGENIN-B1 GENE
    CHANG, TC
    NARDULLI, AM
    LEW, D
    SHAPIRO, DJ
    [J]. MOLECULAR ENDOCRINOLOGY, 1992, 6 (03) : 346 - 354
  • [9] Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen
    Chen, Z
    Yuhanna, IS
    Galcheva-Gargova, Z
    Karas, RH
    Mendelsohn, RE
    Shaul, PW
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1999, 103 (03) : 401 - 406
  • [10] CHARACTERIZATION AND COLOCALIZATION OF STEROID BINDING AND DIMERIZATION ACTIVITIES IN THE MOUSE ESTROGEN-RECEPTOR
    FAWELL, SE
    LEES, JA
    WHITE, R
    PARKER, MG
    [J]. CELL, 1990, 60 (06) : 953 - 962