scholarly journals Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease

2018 ◽  
Vol 20 (1) ◽  
pp. 79 ◽  
Author(s):  
Jeremy Baker ◽  
Ilayda Ozsan ◽  
Santiago Rodriguez Ospina ◽  
Danielle Gulick ◽  
Laura Blair
Keyword(s):  
Stress Response ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Receptor ◽  
Steroid Hormone Receptors ◽  
Psychiatric Disease ◽  
Post Traumatic Stress ◽  
Fk506 Binding Protein ◽  
Structural Regulation ◽  
And Function

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed.

Antiandrogens as environmental endocrine disruptors¤

1998 ◽  
Vol 10 (1) ◽  
pp. 105 ◽  
Author(s):  
W. R. Kelce ◽  
L. E. Gray ◽  
E. M. Wilson
Keyword(s):  
Androgen Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Sex Differentiation ◽  
Environmental Chemicals ◽  
Steroid Hormone Receptors ◽  
Environmental Endocrine Disruptors ◽  
And Function

Steroid hormone receptors control fundamental events in embryonic development and sex differentiation through their function as ligand-inducible transcription factors. The consequences of disrupting these processes can be especially profound during development due to the crucial role hormones play in controlling transient and irreversible developmental processes. Several environmental chemicals, including metabolites of the fungicide vinclozolin and the pesticide DDT, disrupt male reproductive development and function by inhibiting androgen receptor mediated events. A variety of in vitro and in vivo approaches have been used to determine the molecular basis of environmental antiandrogen toxicity. These chemicals commonly bind androgen receptor with moderate affinity and act as antagonists by inhibiting transcription of androgen dependent genes.

Steroid hormone receptors: Cloning, structure and function

1986 ◽  
Vol 25 ◽  
pp. 97
Author(s):  
S. Green ◽  
P. Walter ◽  
V. Kumar ◽  
A. Krust ◽  
P. Argos ◽  
...  
Keyword(s):  
Hormone Receptors ◽  
Steroid Hormone ◽  
Structure And Function ◽  
Steroid Hormone Receptors ◽  
And Function

scholarly journals Isoform-Specific Transcriptional Regulation by Thyroid Hormone Receptors: Hormone-Independent Activation Operates through a Steroid Receptor Mode of Coactivator Interaction

2001 ◽  
Vol 15 (7) ◽  
pp. 1170-1185 ◽  
Author(s):  
Zhihong Yang ◽  
Martin L. Privalsky
Keyword(s):  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Expression Patterns ◽  
Steroid Receptor ◽  
Steroid Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Interaction Domain ◽  
Specific Expression

Abstract Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors that play important roles in vertebrate homeostasis, differentiation, and development. T3Rs are synthesized as multiple isoforms that display tissue-specific expression patterns and distinct transcriptional properties. Most T3R isoforms associate with coactivator proteins and mediate transcriptional activation only in the presence of thyroid hormone. The pituitary-specific T3Rβ-2 isoform departs from this general rule and is able to interact with p160 coactivators, and to mediate transcriptional activation in both the absence and presence of hormone. We report here that this hormone-independent activation is mediated by contacts between the unique N terminus of T3Rβ-2 and an internal interaction domain in the SRC-1 (steroid receptor coactivator-1) and GRIP-1 (glucocorticoid receptor interacting protein 1) coactivators. These hormone-independent contacts between T3Rβ-2 and the p160 coactivators are distinct in sequence and function from the LXXLL motifs that mediate hormone-dependent transcriptional activation and resemble instead a mode of coactivator recruitment previously observed only for the steroid hormone receptors and only in the presence of steroid hormone. Our results suggest that the transcriptional properties of the different T3R isoforms represent a combinatorial mixture of repression, antirepression, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome.

Structure and function of the dioxin receptor: A DNA-binding protein similar to steroid hormone receptors

Chemosphere ◽  
1987 ◽  
Vol 16 (8-9) ◽  
pp. 1681-1686
Author(s):  
Lorenz Poellinger ◽  
Anna Wilhelmsson ◽  
Scott Cuthill ◽  
Johan Lund ◽  
Peter Söderkvist ◽  
...  
Keyword(s):  
Dna Binding ◽  
Hormone Receptors ◽  
Binding Protein ◽  
Steroid Hormone ◽  
Dna Binding Protein ◽  
Structure And Function ◽  
Steroid Hormone Receptors ◽  
And Function ◽  
Dioxin Receptor

scholarly journals Allosteric Modulators of Steroid Hormone Receptors: Structural Dynamics and Gene Regulation

2012 ◽  
Vol 33 (2) ◽  
pp. 271-299 ◽  
Author(s):  
Raj Kumar ◽  
Iain J. McEwan
Keyword(s):  
Transcription Factors ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Steroid Hormone ◽  
Allosteric Regulation ◽  
Steroid Hormone Receptors ◽  
Receptor Proteins ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
And Function

Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action.

scholarly journals The Ubiquitin-Conjugating Enzyme UBCH7 Acts as a Coactivator for Steroid Hormone Receptors

2004 ◽  
Vol 24 (19) ◽  
pp. 8716-8726 ◽  
Author(s):  
Seema Verma ◽  
Ayesha Ismail ◽  
Xiuhua Gao ◽  
Guilian Fu ◽  
Xiaotao Li ◽  
...  
Keyword(s):  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Receptor ◽  
Steroid Hormone Receptors ◽  
Proper Function ◽  
Dependent Manner ◽  
Ubiquitin Conjugating Enzyme ◽  
Receptor Transactivation ◽  
Conjugating Enzyme

ABSTRACT We investigated the role of the ubiquitin-conjugating enzyme UBCH7 in nuclear receptor transactivation. Using transient transfection assays, we demonstrated that UBCH7 modulates the transcriptional activity of progesterone receptor (PR) and glucocorticoid, androgen, and retinoic acid receptors in a hormone-dependent manner and that the ubiquitin conjugation activity of UBCH7 is required for its ability to potentiate transactivation by steroid hormone receptors (SHR). However, UBCH7 showed no significant effect on the transactivation functions of p53 and VP-16 activation domain. Depletion of endogenous UBCH7 protein by small interfering RNAs suggests that UBCH7 is required for the proper function of SHR. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of UBCH7 onto estrogen receptor- and PR-responsive promoters. Additionally, we show that UBCH7 and E6-associated protein (E6-AP) synergistically enhance PR transactivation. We also demonstrate that UBCH7 interacts with steroid receptor coactivator 1 (SRC-1) and that UBCH7 coactivation function is dependent on SRC-1. Taken together, our results reveal the possible role of UBCH7 in steroid receptor transactivation and provide insights into the mechanism of action of UBCH7 in receptor function.

scholarly journals Roles of steroid receptors in the lung and COVID-19

2021 ◽  
Author(s):  
Damien A. Leach ◽  
Greg N. Brooke ◽  
Charlotte L. Bevan
Keyword(s):  
Host Cell ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Current Knowledge ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Proteins ◽  
Transmembrane Serine Protease ◽  
And Function

Abstract COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung – notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.

scholarly journals Cross-Talk between Nuclear Factor-κB and the Steroid Hormone Receptors: Mechanisms of Mutual Antagonism

1998 ◽  
Vol 12 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Lorraine I. McKay ◽  
John A. Cidlowski
Keyword(s):  
Hormone Receptors ◽  
Inflammatory Responses ◽  
Steroid Hormone ◽  
Steroid Receptor ◽  
Nuclear Factor Κb ◽  
Steroid Hormone Receptors ◽  
Receptor Interaction ◽  
Nuclear Factor ◽  
Mutual Antagonism ◽  
A Cell

Abstract Nuclear factor κB (NF-κB) is an inducible transcription factor that positively regulates the expression of proimmune and proinflammatory genes, while glucocorticoids are potent suppressors of immune and inflammatory responses. NF-κB and the glucocorticoid receptor (GR) physically interact, resulting in repression of NF-κB transactivation. In transient cotransfection experiments, we demonstrate a dose-dependent, mutual antagonism between NF-κB and GR. Functional dissection of the NF-κB p50 and p65 subunits and deletion mutants of GR indicate that the GR antagonism is specific to the p65 subunit of NF-κB heterodimer, whereas multiple domains of GR are essential to repress p65-mediated transactivation. Despite its repression of GR transactivation, p65 failed to block the transrepressive GR homologous down-regulation function. We also demonstrate that negative interactions between p65 and GR are not selective for GR, but also occur between NF-κB and androgen, progesterone B, and estrogen receptors. However, although each of these members of the steroid hormone receptor family is repressed by NF-κB, only GR effectively inhibits p65 transactivation. Further, in cotransfections using a chimeric estrogen-GR, the presence of the GR DNA-binding domain is insufficient to confer mutual antagonism to the p65-estrogen receptor interaction. Selectivity of p65 repression for each steroid receptor is demonstrated by IκB rescue from NF-κB-mediated inhibition. Together these data suggest that NF-κB p65 physically interacts with multiple steroid hormone receptors, and this interaction is sufficient to transrepress each steroid receptor. Further, the NF-κB status of a cell has the potential to significantly alter multiple steroid signaling pathways within that cell.

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