BAG-1 diversely affects steroid receptor activity

2011 ◽  
Vol 441 (1) ◽  
pp. 297-303 ◽  
Author(s):  
Regina T. Knapp ◽  
Andrea Steiner ◽  
Ulrike Schmidt ◽  
Kathrin Hafner ◽  
Florian Holsboer ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Heat Shock ◽  
Heat Shock Protein 70 ◽  
Mineralocorticoid Receptor ◽  
Transcriptional Activity ◽  
Steroid Receptors ◽  
Steroid Receptor ◽  
Receptor Activity ◽  
High Homology ◽  
Shed Light

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.

scholarly journals Isolation and identification of l-dopa decarboxylase as a protein that binds to and enhances transcriptional activity of the androgen receptor using the repressed transactivator yeast two-hybrid system

2003 ◽  
Vol 375 (2) ◽  
pp. 373-383 ◽  
Author(s):  
Latif A. WAFA ◽  
Helen CHENG ◽  
Mira A. RAO ◽  
Colleen C. NELSON ◽  
Michael COX ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Transcriptional Activity ◽  
Steroid Receptor ◽  
Receptor Activity ◽  
Dopa Decarboxylase ◽  
Interacting Proteins ◽  
Yeast Two Hybrid ◽  
Hybrid Analysis ◽  
Two Hybrid

The AR (androgen receptor) is a ligand-regulated transcription factor, which belongs to the steroid receptor family and plays an essential role in growth and development of the prostate. Transcriptional activity of steroid receptors is modulated by interaction with co-regulator proteins and yeast two-hybrid analysis is commonly used to identify these steroid receptor-interacting proteins. However, a limitation of conventional two-hybrid systems for detecting AR protein partners has been that they only allow for analysis of the ligand- and DNA-binding domains of the receptor, as its NTD (N-terminal domain) possesses intrinsic transactivation activity. To identify AR N-terminus-interacting proteins, its NTD was used in the RTA (repressed transactivator) system, which is specifically designed for transactivator bait proteins and was shown to be suitable for two-hybrid analysis with the AR NTD. DDC (l-dopa decarboxylase) was detected multiple times as a novel AR-interacting protein, which was subsequently confirmed in vitro and in vivo. Furthermore, transient transfection of DDC in prostate cancer cells strongly enhanced ligand-dependent AR transcriptional activity, an effect that was antagonized using high concentrations of the anti-androgen bicalutamide. Glucocorticoid receptor activity was also strongly enhanced with DDC co-transfection, while oestrogen receptor activity was only mildly affected. Together, our data demonstrate that DDC interacts with AR to enhance steroid receptor transactivation, which may have important implications in prostate cancer progression.

scholarly journals Cooperative Interactions between Androgen Receptor (AR) and Heat-Shock Protein 27 Facilitate AR Transcriptional Activity

2007 ◽  
Vol 67 (21) ◽  
pp. 10455-10465 ◽  
Author(s):  
Amina Zoubeidi ◽  
Anousheh Zardan ◽  
Eliana Beraldi ◽  
Ladan Fazli ◽  
Richard Sowery ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Transcriptional Activity ◽  
Heat Shock Protein 27 ◽  
Cooperative Interactions

scholarly journals Heat shock protein 70 inhibitors suppress androgen receptor expression in LNC aP95 prostate cancer cells

2017 ◽  
Vol 108 (9) ◽  
pp. 1820-1827 ◽  
Author(s):  
Kazuaki Kita ◽  
Masayuki Shiota ◽  
Masako Tanaka ◽  
Asuka Otsuka ◽  
Masaki Matsumoto ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cancer Cells ◽  
Heat Shock Protein 70 ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Prostate Cancer Cells

Heat Shock Protein 70 and Sex Steroid Receptors in the Follicular Structures of Induced Ovarian Cysts

2009 ◽  
Vol 44 (5) ◽  
pp. 805-814 ◽  
Author(s):  
NR Salvetti ◽  
C Baravalle ◽  
GA Mira ◽  
EJ Gimeno ◽  
BE Dallard ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Steroid Receptors ◽  
Sex Steroid ◽  
Ovarian Cysts ◽  
Sex Steroid Receptors

scholarly journals Histone Deacetylase 6–Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2515-2532 ◽  
Author(s):  
Rubén Jiménez-Canino ◽  
Fabián Lorenzo-Díaz ◽  
Frederic Jaisser ◽  
Nicolette Farman ◽  
Teresa Giraldez ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mineralocorticoid Receptor ◽  
Transcriptional Activity ◽  
Adipocyte Differentiation ◽  
Steroid Receptors ◽  
Biological Effects ◽  
Sodium Reabsorption ◽  
Histone Deacetylase 6 ◽  
Cellular Dynamics ◽  
Hsp 90

The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell.

scholarly journals Reduction of Coactivator Expression by Antisense Oligodeoxynucleotides Inhibits ERα Transcriptional Activity and MCF-7 Proliferation

2002 ◽  
Vol 16 (2) ◽  
pp. 253-270 ◽  
Author(s):  
Ilaria T. R. Cavarretta ◽  
Ratna Mukopadhyay ◽  
David M. Lonard ◽  
Lex M. Cowsert ◽  
C. Frank Bennett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Activity ◽  
Steroid Receptors ◽  
Biological Effects ◽  
Steroid Receptor ◽  
Transient Transfection ◽  
Antisense Oligodeoxynucleotides ◽  
Steroid Receptor Coactivator ◽  
Mcf 7

Abstract Steroid receptor RNA activator (SRA) is a novel coactivator for steroid receptors that acts as an RNA molecule, whereas steroid receptor coactivator (SRC) family members, such as steroid receptor coactivator-1 (SRC-1) and transcriptional intermediary factor 2 (TIF2) exert their biological effects as proteins. Individual overexpression of each of these coactivators, which can form multimeric complexes in vivo, results in stimulated ERα transcriptional activity in transient transfection assays. However there is no information on the consequences of reducing SRC-1, TIF2, or SRA expression, singly or in combination, on ERα transcriptional activity. We therefore developed antisense oligodeoxynucleotides (asODNs) to SRA, SRC-1, and TIF2 mRNAs, which rapidly and specifically reduced the expression of each of these coactivators. ERα-dependent gene expression was reduced in a dose-dependent fashion by up to 80% in cells transfected with these oligonucleotides. Furthermore, treatment of cells with combinations of SRA, SRC-1, and TIF2 asODNs reduced ERα transcriptional activity to an extent greater than individual asODN treatment alone, suggesting that these coactivators cooperate, in at least an additive fashion, to activate ERα-dependent target gene expression. Finally, treatment of MCF-7 cells with asODN against SRC-1 and TIF2 revealed a requirement of these coactivators, but not SRA, for hormone-dependent DNA synthesis and induction of estrogen-dependent pS2 gene expression, indicating that SRA and SRC family coactivators can fulfill specific functional roles. Taken together, we have developed a rapid method to reduce endogenous coactivator expression that enables an assessment of the in vivo role of specific coactivators on ERα biological action and avoids potential artifacts arising from overexpression of coactivators in transient transfection assays.

scholarly journals Testosterone Is Required for Delayed Cardioprotection and Enhanced Heat Shock Protein 70 Expression Induced by Preconditioning

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4569-4577 ◽  
Author(s):  
Jing Liu ◽  
Sharon Tsang ◽  
Tak Ming Wong
Keyword(s):  
Androgen Receptor ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Ventricular Myocytes ◽  
Metabolic Inhibition ◽  
Testosterone Replacement ◽  
Sham Operation ◽  
Isolated Hearts ◽  
Delayed Cardioprotection

Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7–8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a κ-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.

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