Caveolin-1 potentiates estrogen receptor α (ERα) signaling -: Caveolin-1 drives ligand-independent nuclear translocation and activation of ERα

被引:126
作者
Schlegel, A
Wang, CG
Katzenellenbogen, BS
Pestell, RG
Lisanti, MP
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
[3] Yeshiva Univ Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA
[4] Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[5] Univ Illinois, Coll Med, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA
[6] Univ Illinois, Coll Med, Dept Cell & Struct Biol, Urbana, IL 61801 USA
关键词
D O I
10.1074/jbc.274.47.33551
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Estrogen receptor alpha (ER alpha) is a soluble protein that mediates the effects of the gonadal estrogens such as 17 beta-estradiol. Upon ligand binding, a cytoplasmic pool of ER alpha translocates to the nucleus, where it acts as a transcription factor, driving the expression of genes that contain estrogen-response elements. The activity of ERa is regulated by a number of proteins, including cytosolic chaperones and nuclear cofactors, Here, we show that caveolin-1 potentiates ER alpha-mediated signal transduction, Coexpression of caveolin-1 and ER alpha resulted in ligand-independent translocation of ER alpha to the nucleus as shown by both cell fractionation and immunofluorescence microscopic studies. Similarly, caveolin-1 augmented both ligand-independent and ligand-dependent ER alpha signaling as measured using a estrogen-response element-based luciferase reporter assay, Caveolin-1-mediated activation of ER alpha was sensitive to a well known ER antagonist, 4-hydroxytamoxifen. However, much higher concentrations of tamoxifen were required to mediate inhibition in the presence of caveolin-1. Interestingly, caveolin-1 expression also synergized with a constitutively active, ligand-independent ER alpha mutant, dramatically illustrating the potent stimulatory effect of caveolin-1 in this receptor system. Taken together, our results identify caveolin-1 as a new positive regulator of ER alpha signal transduction.
引用
收藏
页码:33551 / 33556
页数:6
相关论文
共 48 条
[1]   Flotillin and epidermal surface antigen define a new family of caveolae-associated integral membrane proteins [J].
Bickel, PE ;
Scherer, PE ;
Schnitzer, JE ;
Oh, P ;
Lisanti, MP ;
Lodish, HF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (21) :13793-13802
[2]   Functions of lipid rafts in biological membranes [J].
Brown, DA ;
London, E .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 :111-136
[3]   Regulation of G protein-coupled receptor kinases by caveolin [J].
Carman, CV ;
Lisanti, MP ;
Benovic, JL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (13) :8858-8864
[4]   Identification of peptide and protein ligands for the caveolin-scaffolding domain - Implications for the interaction of caveolin with caveolae-associated proteins [J].
Couet, J ;
Li, SW ;
Okamoto, T ;
Ikezu, T ;
Lisanti, MP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (10) :6525-6533
[5]   Bradykinin sequesters B2 bradykinin receptors and the receptor-coupled G alpha subunits G alpha(q) and G alpha(i) in caveolae in DDT1 MF-2 smooth muscle cells [J].
deWeerd, WFC ;
LeebLundberg, LMF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (28) :17858-17866
[6]   Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo - A role for the caveolin-scaffolding domain [J].
Engelman, JA ;
Chu, C ;
Lin, A ;
Jo, H ;
Ikezu, T ;
Okamoto, T ;
Kohtz, DS ;
Lisanti, MP .
FEBS LETTERS, 1998, 428 (03) :205-211
[7]   Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis [J].
Engelman, JA ;
Lisanti, MP ;
Scherer, PE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (48) :32111-32120
[8]   Molecular genetics of the caveolin gene family:: Implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy [J].
Engelman, JA ;
Zhang, XL ;
Galbiati, F ;
Volonté, D ;
Sotgia, F ;
Pestell, RG ;
Minetti, C ;
Scherer, PE ;
Okamoto, T ;
Lisanti, MP .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 63 (06) :1578-1587
[9]   Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo -: Implications for human breast cancer [J].
Engelman, JA ;
Lee, RJ ;
Karnezis, A ;
Bearss, DJ ;
Webster, M ;
Siegel, P ;
Muller, WJ ;
Windle, JJ ;
Pestell, RG ;
Lisanti, MP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (32) :20448-20455
[10]   Recombinant expression of caveolin-1 in oncogenically transformed cells abrogates anchorage-independent growth [J].
Engelman, JA ;
Wykoff, CC ;
Yasuhara, S ;
Song, KS ;
Okamoto, T ;
Lisanti, MP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (26) :16374-16381