Estrogen receptor β acts as a dominant regulator of estrogen signaling

被引:299
作者
Pettersson, K [1 ]
Delaunay, F [1 ]
Gustafsson, JÅ [1 ]
机构
[1] Karolinska Inst, Novum, Dept Med Nutr, S-14186 Huddinge, Sweden
关键词
ER alpha; ER beta; heterodimerization; agonists; antagonists;
D O I
10.1038/sj.onc.1203828
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
The physiological effects of estrogens are mediated by two intracellular transcription factors, the estrogen receptors (ERs), that regulate transcription of target genes through binding to specific DNA target sequences. Here we describe alterations in cellular responses to different ER agonists and to the anti-estrogenic compound tamoxifen resulting from co-expression of the two ERs in transient co-transfection experiments. Our results demonstrate that ER beta can act as a negative or positive dominant regulator of ER activity. This is manifested through reduced transcriptional activity at low concentrations of estradiol (E-2); increased antagonistic effects of tamoxifen on E-2 stimulated activity; and enhanced agonistic action of the phytoestrogenic compound genistein, Furthermore, using chimeric proteins lacking the N-terminal activation function 1 (AF-1), we show that the differential responses of ER alpha and ER beta to different agonists and antagonists are primarily dictated by inherent differences in the C-terminal ligand-binding domains of the receptors, whereas the magnitude of transcriptional activity is influenced by ER alpha AF-1, but not ER beta AF-1, The ER alpha AF-1 activity appears to be modulated upon co-expression of both ERs, The alterations in transcriptional activity resulting from co-expression of ER alpha and ER beta are probably due to the formation of alpha/beta heterodimeric complexes, This study demonstrates that co-localization and subsequent heterodimerization of ER alpha and ER beta may result in receptor activity distinct from that of ER homodimers.
引用
收藏
页码:4970 / 4978
页数:9
相关论文
共 39 条
[1]   Differential response of estrogen receptor α and estrogen receptor β to partial estrogen agonists/antagonists [J].
Barkhem, T ;
Carlsson, B ;
Nilsson, Y ;
Enmark, E ;
Gustafsson, JÅ ;
Nilsson, S .
MOLECULAR PHARMACOLOGY, 1998, 54 (01) :105-112
[2]   Control of transcription by steroid hormones [J].
Beato, M ;
Truss, M ;
Chavez, S .
BASIS FOR CANCER MANAGEMENT, 1996, 784 :93-123
[3]   ROLE OF THE 2 ACTIVATING DOMAINS OF THE ESTROGEN-RECEPTOR IN THE CELL-TYPE AND PROMOTER-CONTEXT DEPENDENT AGONISTIC ACTIVITY OF THE ANTIESTROGEN 4-HYDROXYTAMOXIFEN [J].
BERRY, M ;
METZGER, D ;
CHAMBON, P .
EMBO JOURNAL, 1990, 9 (09) :2811-2818
[4]   Androgen and glucocorticoid receptor heterodimer formation - A possible mechanism for mutual inhibition of transcriptional activity [J].
Chen, SY ;
Wang, J ;
Yu, GQ ;
Liu, WH ;
Pearce, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (22) :14087-14092
[5]   Estrogen receptors and cell proliferation in breast cancer [J].
Ciocca, DR ;
Fanelli, MA .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 1997, 8 (08) :313-321
[6]   Estrogen receptors alpha and beta form heterodimers on DNA [J].
Cowley, SM ;
Hoare, S ;
Mosselman, S ;
Parker, MG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (32) :19858-19862
[7]  
Dotzlaw H, 1999, CANCER RES, V59, P529
[8]   The vascular protective effects of estrogen [J].
Farhat, MY ;
Lavigne, MC ;
Ramwell, PW .
FASEB JOURNAL, 1996, 10 (05) :615-624
[9]   NUCLEAR HORMONE RECEPTORS ACTIVATE DIRECT, INVERTED, AND EVERTED REPEATS [J].
FORMAN, BM ;
EVANS, RM .
STEROID RECEPTORS AND ANTIHORMONES, 1995, 761 :29-37
[10]   Cardiac myocytes and fibroblasts contain functional estrogen receptors [J].
Grohe, C ;
Kahlert, S ;
Lobbert, K ;
Stimpel, M ;
Karas, RH ;
Vetter, H ;
Neyses, L .
FEBS LETTERS, 1997, 416 (01) :107-112