title: BAG-1 diversely affects steroid receptor activity.
abstract: Part of the cellular and physiological functions of BAG-1 (Bcl-2-associated athanogene 1) has been ascribed to the ability of this hsp70 (heat-shock protein 70) co-chaperone to regulate steroid receptor activity. BAG-1 has been reported to inhibit the GR (glucocorticoid receptor) and stimulate the androgen receptor, but to leave the activity of the MR (mineralocorticoid receptor) unchanged. Given the high homology between the MR and GR, this disparity in the actions of BAG-1 is surprising. In the present study, we analysed the effect of BAG-1 on the activity of the closely related PR (progesterone receptor). Similarly to the GR, the transcriptional activity of the PR is inhibited by the long and middle isoforms of BAG-1, BAG-1L and BAG-1M, but not by the short isoform, BAG-1S. We found this inhibition to require the hsp70-binding domain of BAG-1. To shed light on the mechanisms that could explain BAG-1's differential actions on steroid receptors, we tested the binding of BAG-1M to the PR. Mutational analyses of the PR and BAG-1M revealed that the mode of interaction and BAG-1M-mediated inhibition of the PR differs from the reported scenario for the GR. Surprisingly, we also found binding of BAG-1M to the MR. In addition, BAG-1M was able to inhibit the transcriptional activity of the MR. These data entail a reappraisal of the physiological actions of BAG-1M on steroid receptor activity.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
authors.forename: Regina T
authors.initials: RT
authors.lastname: Knapp
authors.forename: Andrea
authors.initials: A
authors.lastname: Steiner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hafner
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D011485:Protein Binding; D020033:Protein Isoforms; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D020033:Protein Isoforms; D011987:Receptors, Steroid; D014157:Transcription Factors