Identification of a new isoform of the human estrogen receptor-alpha (hER-α) that is encoded by distinct transcripts and that is able to repress hER-α activation function 1

被引:337
作者
Flouriot, G
Brand, H
Denger, S
Metivier, R
Kos, M
Reid, G
Sonntag-Buck, V
Gannon, F
机构
[1] EMBL, D-69117 Heidelberg, Germany
[2] CNRS, UPRESA 6026, F-35042 Rennes, France
关键词
activation functions; estrogen receptor; gene regulation; isoforms; MCF7;
D O I
10.1093/emboj/19.17.4688
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
A new isoform of the human estrogen receptor-alpha (hER-alpha) has been identified and characterized. This 46 kDa isoform (hER alpha 46) lacks the N-terminal 173 amino acids present in the previously characterized 66 kDa isoform (hER alpha 66). hER alpha 46 is encoded by a new class of hER-alpha transcript that lacks the first coding exon (exon 1A) of the ER-alpha gene. We demonstrated that these Delta 1A hER-alpha transcripts originate from the E and F hER-alpha promoters and are produced by the splicing of exon 1E directly to exon 2. Functional analysis of hER alpha 46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is an effective ligand-inducible transcription factor. In contrast, hER alpha 46 is a powerful inhibitor of hER alpha 66 in a cell context where the transactivating function of AF-1 predominates over AF-2. The mechanisms by which the AF-1 dominant-negative action is exerted may involve heterodimerization of the two receptor isoforms and/or direct competition for the ER-alpha DNA-binding site. hER alpha 66/ hER alpha 46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hER alpha 46 in cellular proliferation.
引用
收藏
页码:4688 / 4700
页数:13
相关论文
共 62 条
[1]   CHARACTERIZATION AND EPITOPE MAPPING OF A NEW PANEL OF MONOCLONAL-ANTIBODIES TO ESTRADIOL-RECEPTOR [J].
ABBONDANZA, C ;
DEFALCO, A ;
NIGRO, V ;
MEDICI, N ;
ARMETTA, I ;
MOLINARI, AM ;
MONCHARMONT, B ;
PUCA, GA .
STEROIDS, 1993, 58 (01) :4-12
[2]   THE ESTROGEN-RECEPTOR [J].
AUCHUS, RJ ;
FUQUA, SAW .
BAILLIERES CLINICAL ENDOCRINOLOGY AND METABOLISM, 1994, 8 (02) :433-449
[3]  
Ausubel FA, 1995, CURRENT PROTOCOLS MO
[4]   A MITOCHONDRIAL RNA MATURASE GENE TRANSFERRED TO THE YEAST NUCLEUS CAN CONTROL MITOCHONDRIAL MESSENGER-RNA SPLICING [J].
BANROQUES, J ;
DELAHODDE, A ;
JACQ, C .
CELL, 1986, 46 (06) :837-844
[5]   Alternative initiation of translation accounts for a 67/45 kDa dimorphism of the human estrogen receptor ERα [J].
Barraille, P ;
Chinestra, P ;
Bayard, F ;
Faye, JC .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 257 (01) :84-88
[6]   GENE-REGULATION BY STEROID-HORMONES [J].
BEATO, M .
CELL, 1989, 56 (03) :335-344
[7]   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
[8]  
BRASIER AR, 1992, METHOD ENZYMOL, V216, P386
[9]  
Clarke RB, 1997, CANCER RES, V57, P4987
[10]   ANALYSIS OF TRANSCRIPTION AND ESTROGEN INSENSITIVITY IN THE FEMALE MOUSE AFTER TARGETED DISRUPTION OF THE ESTROGEN-RECEPTOR GENE [J].
COUSE, JF ;
CURTIS, SW ;
WASHBURN, TF ;
LINDZEY, J ;
GOLDING, TS ;
LUBAHN, DB ;
SMITHIES, O ;
KORACH, KS .
MOLECULAR ENDOCRINOLOGY, 1995, 9 (11) :1441-1454