Roles of steroid receptors in the lung and COVID-19

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.

Download Full-text

Phasing the intranuclear organization of steroid hormone receptors

Biochemical Journal ◽

10.1042/bcj20200883 ◽

2021 ◽

Vol 478 (2) ◽

pp. 443-461

Author(s):

Martin Stortz ◽

Diego M. Presman ◽

Adali Pecci ◽

Valeria Levi

Keyword(s):

Drug Targets ◽

Hormone Receptors ◽

Steroid Receptors ◽

Current Knowledge ◽

Steroid Hormone Receptors ◽

New Paradigm ◽

Theoretical Frameworks ◽

New Ideas ◽

And Function ◽

Liquid Liquid Phase Separation

Steroid receptors (SRs) encompass a family of transcription factors that regulate the expression of thousands of genes upon binding to steroid hormones and include the glucocorticoid, androgen, progesterone, estrogen and mineralocorticoid receptors. SRs control key physiological and pathological processes, thus becoming relevant drug targets. As with many other nuclear proteins, hormone-activated SRs concentrate in multiple discrete foci within the cell nucleus. Even though these foci were first observed ∼25 years ago, their exact structure and function remained elusive. In the last years, new imaging methodologies and theoretical frameworks improved our understanding of the intranuclear organization. These studies led to a new paradigm stating that many membraneless nuclear compartments, including transcription-related foci, form through a liquid–liquid phase separation process. These exciting ideas impacted the SR field by raising the hypothesis of SR foci as liquid condensates involved in transcriptional regulation. In this work, we review the current knowledge about SR foci formation under the light of the condensate model, analyzing how these structures may impact SR function. These new ideas, combined with state-of-the-art techniques, may shed light on the biophysical mechanisms governing the formation of SR foci and the biological function of these structures in normal physiology and disease.

Download Full-text

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

Endocrine Reviews ◽

10.1210/er.2011-1033 ◽

2012 ◽

Vol 33 (2) ◽

pp. 271-299 ◽

Cited By ~ 80

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.

Download Full-text

Regulation of Steroid Hormone Receptors and Coregulators during the Cell Cycle Highlights Potential Novel Function in Addition to Roles as Transcription Factors

Nuclear Receptor Signaling ◽

10.1621/nrs.14001 ◽

2016 ◽

Vol 14 (1) ◽

pp. nrs.14001 ◽

Cited By ~ 5

Author(s):

Yingfeng Zheng ◽

Leigh C. Murphy

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Transcriptional Activity ◽

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Cycle Progression ◽

Expression Of Genes ◽

Cycle Regulation

Cell cycle progression is tightly controlled by several kinase families including Cyclin-Dependent Kinases, Polo-Like Kinases, and Aurora Kinases. A large amount of data show that steroid hormone receptors and various components of the cell cycle, including cell cycle regulated kinases, interact, and this often results in altered transcriptional activity of the receptor. Furthermore, steroid hormones, through their receptors, can also regulate the transcriptional expression of genes that are required for cell cycle regulation. However, emerging data suggest that steroid hormone receptors may have roles in cell cycle progression independent of their transcriptional activity. The following is a review of how steroid receptors and their coregulators can regulate or be regulated by the cell cycle machinery, with a particular focus on roles independent of transcription in G2/M.

Download Full-text

Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01550 ◽

2005 ◽

Vol 34 (2) ◽

pp. 517-534 ◽

Cited By ~ 39

Author(s):

S Hombach-Klonisch ◽

A Kehlen ◽

P A Fowler ◽

B Huppertz ◽

J F Jugert ◽

...

Keyword(s):

Epithelial Cells ◽

Estrogen Receptor Alpha ◽

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Three Dimensional ◽

Steroid Hormone Receptors ◽

Endogenous Estrogen ◽

Endometrial Epithelial Cells

Information on the regulation of steroid hormone receptors and their distinct functions within the human endometrial epithelium is largely unavailable. We have immortalized human primary endometrial epithelial cells (EECs) isolated from a normal proliferative phase endometrium by stably transfecting the catalytic subunit (hTERT) of the human telomerase complex and cultured these hTERT-EECs now for over 350 population doublings. Active hTERT was detected in hTERT-EECs employing the telomerase repeat amplification assay protocol. hTERT-EECs revealed a polarized, non-invasive epithelial phenotype with apical microvilli and production of a basal lamina when grown on a three-dimensional collagen–fibroblast lattice. Employing atomic force microscopy, living hTERT-EECs were shown to produce extracellular matrix (ECM) components and ECM secretion was modified by estrogen and progesterone (P4). hTERT-EECs expressed inducible and functional endogenous estrogen receptor-alpha (ER-alpha) as demonstrated by estrogen response element reporter assays and induction of P4 receptor (PR). P4 treatment down-regulated PR expression, induced MUC-1 gene activity and resulted in increased ER-beta transcriptional activity. Gene activities of cytokines and their receptors interleukin (IL)-6, leukemia inhibitory factor (LIF), IL-11 and IL-6 receptor (IL6-R), LIF receptor and gp130 relevant to implantation revealed a 17 beta-estradiol (E2)-mediated up-regulation of IL-6 and an E2- and P4-mediated up-regulation of IL6-R in hTERT-EECs. Thus, hTERT-EECs may be regarded as a novel in vitro model to investigate the role of human EECs in steroid hormone-dependent normal physiology and pathologies, including implantation failure, endometriosis and endometrial cancer.

Download Full-text

Steroid hormone receptors: Basic and clinical aspects—Proceedings meadowbrook conference on steroid receptors

Trends in Endocrinology and Metabolism ◽

10.1016/1043-2760(94)90086-8 ◽

1994 ◽

Vol 5 (5) ◽

pp. 223-225

Author(s):

Edwin R. Sánchez

Keyword(s):

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Clinical Aspects

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms20010079 ◽

2018 ◽

Vol 20 (1) ◽

pp. 79 ◽

Cited By ~ 11

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.

Download Full-text

A conserved mechanism of sirtuin signalling through steroid hormone receptors

Bioscience Reports ◽

10.1042/bsr20193535 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 3

Author(s):

Henry K. Bayele

Keyword(s):

Drug Targets ◽

Metabolic Regulation ◽

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Nuclear Receptor Coregulators ◽

Dafachronic Acid ◽

Important Drug

Abstract SIRT1 and orthologous sirtuins regulate a universal mechanism of ageing and thus determine lifespan across taxa; however, the precise mechanism remains vexingly polemical. They also protect against many metabolic and ageing-related diseases by dynamically integrating several processes including autophagy, proteostasis, calorie restriction, circadian rhythmicity and metabolism. These sirtuins are therefore important drug targets particularly because they also transduce allosteric signals from sirtuin-activating compounds such as resveratrol into increased healthspan in evolutionarily diverse organisms. While many of these functions are apparently regulated by deacetylation, that mechanism may not be all-encompassing. Since gonadal signals have been shown to regulate ageing/lifespan in worms and flies, the present study hypothesized that these sirtuins may act as intermediary factors for steroid hormone signal transduction. Accordingly, SIRT1 and its orthologues, Sir2 and Sir-2.1, are shown to be veritable nuclear receptor coregulators that classically coactivate the oestrogen receptor in the absence of ligand; coactivation was further increased by 17β-oestradiol. Remarkably in response to the worm steroid hormone dafachronic acid, SIRT1 reciprocally coactivates DAF-12, the steroid receptor that regulates nematode lifespan. These results suggest that steroid hormones may co-opt and modulate a phyletically conserved mechanism of sirtuin signalling through steroid receptors. Hence, it is interesting to speculate that certain sirtuin functions including prolongevity and metabolic regulation may be mechanistically linked to this endocrine signalling pathway; this may also have implications for understanding the determinative role of gonadal steroids such as oestradiol in human ageing. At its simplest, this report shows evidence for a hitherto unknown deacetylation-independent mechanism of sirtuin signalling.

Download Full-text

Antiandrogens as environmental endocrine disruptors¤

Reproduction Fertility and Development ◽

10.1071/r98051 ◽

1998 ◽

Vol 10 (1) ◽

pp. 105 ◽

Cited By ~ 108

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.

Download Full-text

The Possible Impact of Obesity on Androgen, Progesterone and Estrogen Receptors (ERα and ERβ) Gene Expression in Breast Cancer Patients

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s7707 ◽

2011 ◽

Vol 5 ◽

pp. BCBCR.S7707 ◽

Cited By ~ 4

Author(s):

R. Jahanban Esfahlan ◽

N. Zarghami ◽

A. Jahanban Esfahlan ◽

M. Mollazadeh ◽

K. Nejati ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Estrogen Receptors ◽

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Mrna Level ◽

Previous History ◽

Steroid Hormone Receptors ◽

Breast Cancer Patients

Background Obesity has been associated with increased mortality from hormone dependant cancers such as breast cancer which is the most prevalent cancer in women. The link between obesity and breast cancer can be attributed to excess estrogen produced through aromatization in adipose tissue. The role of steroid hormone receptors in breast cancer development is well studied but how obesity can affect the expression pattern of steroid hormones in patients with different grades of breast cancer was the aim of this study. Methods In this case-control study, 70 women with breast cancer participated with different grades of obesity (36 none obese, BMI < 25 kg/m2 and 34 obese, BMI ≥ 25 kg/m2). The mean age of participants was 44.53 ± 1.79 yr (21–70 yr). The serum level of estrogen, progesterone and androgen determined by ELISA. Following quantitative expression of steroid hormone receptors mRNA in tumor tissues evaluated by Real-time PCR. Patients with previous history of radiotherapy or chemotherapy were excluded. SPSS 16 was used for data analysis and P < 0.05 considered statistically significant. Results The difference in ERα, ERβ and PR mRNA level between normal and obese patients was significant ( P < 0.001). In addition, the expression of AR mRNA was found to be higher than other steroid receptors. There was no significant relation between ERβ gene expression in two groups ( P = 0.68). We observed a significant relationship between ERα and AR mRNA with tumor stage and tumor grade, respectively ( P = 0.023, P = 0.015). Conclusion According to the obtained results, it is speculated that obesity could paly a significant role in estrogen receptors gene expression and also could affect progression and proliferation of breast cancer cells.

Download Full-text