Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1.
A new isoform of the human estrogen receptor-alpha (hER-alpha) has been identified and characterized. This 46 kDa isoform (hERalpha46) lacks the N-terminal 173 amino acids present in the previously characterized 66 kDa isoform (hERalpha66). hERalpha46 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 Delta1A 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 hERalpha46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is an effective ligand-inducible transcription factor. In contrast, hERalpha46 is a powerful inhibitor of hERalpha66 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 heterodimeri zation of the two receptor isoforms and/or direct competition for the ER-alpha DNA-binding site. hERalpha66/hERalpha46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hERalpha46 in cellular proliferation.
Flouriot
G
G
EMBL, Meyerhofstrabetae 1, D-69117 Heidelberg, Germany and Endocrinologie Moléculaire de la Reproduction, UPRES-A CNRS 6026, Campus de Beaulieu, 35042 Rennes cedex, France.
Brand
H
H
Denger
S
S
Metivier
R
R
Kos
M
M
Reid
G
G
Sonntag-Buck
V
V
Gannon
F
F
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D004247:DNA; D019281:Dimerization; D047628:Estrogen Receptor alpha; D006801:Humans; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D011960:Receptors, Estrogen / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004247:DNA