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Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor

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Abstract

Steroid hormone receptors are a class of cell-specific trans-acting transcription regulatory factors whose activity is controlled by specific binding of the hormone. The hormone-receptor complex appears to associate with promoter/enhancer elements of specific target genes, resulting in activation of transcription (see refs 1 and 2 for reviews). Sequence comparison between the oestrogen3,4, glucocorticoid5,6 and progesterone receptors (refs 7,8 and unpublished results) and site-directed mutation analysis9–11, has identified in each at least two functional domains important for steroid receptor function. Region E (Fig. la), is the hormone-binding domain9; region C is a 66-amino-acid region (Figs la,b) that is more highly conserved than the hormone-binding domain and has the potential to form at least two zinc-stabilized 'DNA-binding fingers' analogous to those proposed for the Xenopus transcription factor TFIIIA7,12,13. We3,4 and others14 have suggested that this region may be the receptor's DNA-binding domain. We show here that point mutations replacing two cysteines by two histidines in the first potential DNA-binding finger of the human oestrogen receptor (hER) prevent it from activating gene transcription. We further show that a chimaeric receptor formed by replacing this 66-amino-acid region of the HER with that of the human glucocorticoid receptor (hGR) activates expression of a glucocorticoid-inducible gene, but not of an oestrogen-inducible gene, in the presence of oestradiol. Thus, region C determines the receptor's specificity for target genes.

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  1. Pierre Chambon: To whom correspondence should be addressed.

Authors and Affiliations

  1. Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique de I'INSERM, Faculté de Médecine, 11, rue Humann, 67085, Strasbourg Cédex, France

    Stephen Green & Pierre Chambon

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  1. Stephen Green
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  2. Pierre Chambon
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Green, S., Chambon, P. Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor. Nature 325, 75–78 (1987). https://doi.org/10.1038/325075a0

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