Molecular mechanism of estrogen receptor (ER)alpha-specific, estradiol-dependent expression of the progesterone receptor (PR) B-isoform.
The physiological effects of progesterone are mediated by the progesterone receptor (PR) isoforms PRA and PRB, transcribed from a single gene, under control of two distinct promoters. Both the isoforms display different, promoter- and cell line-specific transactivation properties. Upregulation of both isoforms in response to estradiol stimulation has been described, although the two promoters contain no classical estrogen response element (ERE). Therefore, we decided to investigate the regulation of PRB-expression through distinct estrogen receptor (ER)-isoforms: ERalpha and ERbeta We demonstrate, that in HeLa cells treated with E2, PRB promoter activity was enhanced (five-fold) by ERalpha, but not by ERbeta. ERbeta was also unable to stimulate activity of the PRB promoter in BT20 and Ishikawa cells, where ERalpha induced reporter activity by two-fold. Deletion of the AF1-but not AF2 domain from ERalpha resulted in loss of the transactivation potential in all cell lines tested. Furthermore, in BT20 cells deletion of the AF2 domain of ERalpha resulted in stronger transcriptional activation than that mediated through wild-type ERalpha. In SK-BR-3 cells both ERs repressed PRB promoter activity and this repression was enhanced by co-transfection of SRC1. However, strong estrogen-dependent stimulation was observed after deletion of AF2. We conclude that PRB expression is stimulated by ERalpha but not ERbeta in an unique, AF1-dependent but AF2-independent mechanism.
Flötotto
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Universitäts-Frauenklinik, Heinrich Heine-Universität, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Niederacher
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D
Hohmann
D
D
Heimerzheim
T
T
Dall
P
P
Djahansouzi
S
S
Bender
H G
HG
Hanstein
B
B
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000502:physiology*; D011980:Receptors, Progesterone / Q000235:genetics*; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D004958:Estradiol