Human estrogen receptor ligand activity inversion mutants: Receptors that interpret antiestrogens as estrogens and estrogens as antiestrogens and discriminate among different antiestrogens

被引:80
作者
Montano, MM
Ekena, K
Krueger, KD
Keller, AL
Katzenellenbogen, BS
机构
[1] UNIV ILLINOIS,DEPT MOLEC & INTEGRAT PHYSIOL,URBANA,IL 61801
[2] UNIV ILLINOIS,DEPT CELL & STRUCT BIOL,URBANA,IL 61801
关键词
D O I
10.1210/me.10.3.230
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The estrogen receptor (ER) is a transcription factor whose activity is normally activated by the hormone estradiol and inhibited by antiestrogen. It has been found that certain mutational changes in the activation function-2 region in the hormone-binding domain of the human ER result in ligand activity inversion mutants, be. receptors that are now activated by antiestrogen and inhibited by estrogen. The ER point mutant L540Q is activated by several antiestrogens (the more pure antiestrogens ICI 164,384 and RU 54,876 or the partial antiestrogen trans-hydroxytamoxifen) but not by estradiol. The presence of the F domain and an intact activation function-1 in the A/B domain are required for this activity, as is the DNA-binding ability of the receptor. This inverted ligand activity is observed with several estrogen-responsive promoters, both simple and complex; however, the activating ability of antiestrogens is observed only in some cells, highlighting the important role of cell-specific factors in ligand interpretation. The introduction of two additional amino acid changes close to 540 results in receptors that are still not activated by estradiol but are now able to distinguish between partial antiestrogens (which remain agonistic) and pure antiestrogens (which show a greatly reduced stimulatory activity. These ligand activity inversion mutants remain stable in cells in the presence of the antiestrogen ICI 164,384, as does a related ER mutant receptor that shows the normal, wild type ER ligand activity profile in which ICI 164,384 is transcriptionally inactive. Thus, the presence of adequate levels of mutant ER may be necessary but not sufficient for ICI 164,384 to elicit transcriptional activity). These findings highlight the means by which the carboxyl-terminal region in domain E functions to interpret the activity of a ligand, and they demonstrate that rather minimal changes in the ER can result in receptors with inverted response to antiestrogen and estrogen. Such point mutations, if present in estrogen target cells, would result in antiestrogens being seen as growth stimulators, rather than suppressors, with potentially detrimental consequences in terms of breast cancer treatment with antiestrogens.
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页码:230 / 242
页数:13
相关论文
共 52 条
[1]   EFFECTS OF ANTIESTROGENS ON THE DNA-BINDING ACTIVITY OF ESTROGEN-RECEPTORS INVITRO [J].
ARBUCKLE, ND ;
DAUVOIS, S ;
PARKER, MG .
NUCLEIC ACIDS RESEARCH, 1992, 20 (15) :3839-3844
[2]   ESTROGEN ACTION VIA THE CAMP SIGNALING PATHWAY - STIMULATION OF ADENYLATE-CYCLASE AND CAMP-REGULATED GENE-TRANSCRIPTION [J].
ARONICA, SM ;
KRAUS, WL ;
KATZENELLENBOGEN, BS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (18) :8517-8521
[3]   GENE-REGULATION BY STEROID-HORMONES [J].
BEATO, M .
CELL, 1989, 56 (03) :335-344
[4]   TRANSCRIPTIONAL ACTIVATION BY THE ESTROGEN-RECEPTOR REQUIRES A CONFORMATIONAL CHANGE IN THE LIGAND-BINDING DOMAIN [J].
BEEKMAN, JM ;
ALLAN, GF ;
TSAI, SY ;
TSAI, MJ ;
OMALLEY, BW .
MOLECULAR ENDOCRINOLOGY, 1993, 7 (10) :1266-1274
[5]   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
[6]  
BROWN M, 1990, J BIOL CHEM, V265, P11238
[7]  
BRUNNER N, 1993, CANCER RES, V53, P3229
[8]   INTERACTION OF PROTEINS WITH TRANSCRIPTIONALLY ACTIVE ESTROGEN-RECEPTORS [J].
CAVAILLES, V ;
DAUVOIS, S ;
DANIELIAN, PS ;
PARKER, MG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (21) :10009-10013
[9]   THE ROLE OF ESTROGEN RESPONSE ELEMENTS IN EXPRESSION OF THE XENOPUS-LAEVIS VITELLOGENIN-B1 GENE [J].
CHANG, TC ;
NARDULLI, AM ;
LEW, D ;
SHAPIRO, DJ .
MOLECULAR ENDOCRINOLOGY, 1992, 6 (03) :346-354
[10]   IDENTIFICATION OF A CONSERVED REGION REQUIRED FOR HORMONE DEPENDENT TRANSCRIPTIONAL ACTIVATION BY STEROID-HORMONE RECEPTORS [J].
DANIELIAN, PS ;
WHITE, R ;
LEES, JA ;
PARKER, MG .
EMBO JOURNAL, 1992, 11 (03) :1025-1033