scholarly journals Proteasomal Inhibition Enhances Glucocorticoid Receptor Transactivation and Alters Its Subnuclear Trafficking

2002 ◽  
Vol 22 (12) ◽  
pp. 4113-4123 ◽  
Author(s):  
Bonnie J. Deroo ◽  
Claudia Rentsch ◽  
Sowmini Sampath ◽  
Janel Young ◽  
Donald B. DeFranco ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Chromatin Remodeling ◽  
Nuclear Matrix ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Proteasome Inhibition ◽  
Factor Loading ◽  
Steroid Hormone Receptors ◽  
Ubiquitin Proteasome ◽  
Subnuclear Trafficking

ABSTRACT The ubiquitin-proteasome pathway regulates the turnover of many transcription factors, including steroid hormone receptors such as the estrogen receptor and progesterone receptor. For these receptors, proteasome inhibition interferes with steroid-mediated transcription. We show here that proteasome inhibition with MG132 results in increased accumulation of the glucocorticoid receptor (GR), confirming that it is likewise a substrate for the ubiquitin-proteasome degradative pathway. Using the mouse mammary tumor virus (MMTV) promoter integrated into tissue culture cells, we found that proteasome inhibition synergistically increases GR-mediated transactivation. This increased activation was observed in a number of cell lines and on various MMTV templates, either as transiently transfected reporters or stably integrated into chromatin. These observations suggest that the increase in GR-mediated transcription due to proteasome inhibition may occur downstream of the initial chromatin remodeling step. In support of this concept, the increase in transcription did not correlate with an increase in chromatin remodeling, as measured by restriction enzyme hypersensitivity, or transcription factor loading, as exemplified by nuclear factor 1. To investigate the relationship between GR turnover, transcription, and subnuclear trafficking, we examined the effect of proteasome inhibition on the mobility of the GR within the nucleus and association of the GR with the nuclear matrix. Blocking GR turnover reduced the mobility of the GR within the nucleus, and this correlated with increased association of the receptor with the nuclear matrix. As a result of proteasome inhibition, GR mobility within the nucleus was reduced while its association with the nuclear matrix was increased. Thus, while altered nuclear mobility of steroid receptors may be a common feature of proteasome inhibition, GR is unique in its enhanced transactivation activity that results when proteasome function is compromised. Proteasomes may therefore impact steroid receptor action at multiple levels and exert distinct effects on individual receptor types.

scholarly journals E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06006 ◽  
Author(s):  
Sivapriya Ramamoorthy ◽  
Zafar Nawaz
Keyword(s):  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Enzymatic Activities ◽  
Steroid Hormone Receptors ◽  
Dual Function ◽  
Biological Functions ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

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

2016 ◽  
Vol 14 (1) ◽  
pp. nrs.14001 ◽  
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.

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

2005 ◽  
Vol 34 (2) ◽  
pp. 517-534 ◽  
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.

Nuclear Matrix Acceptor Binding Sites for Steroid Hormone Receptors: A Candidate Nuclear Matrix Acceptor Protein

1996 ◽  
pp. 337-376 ◽  
Author(s):  
Andrea H. Lauber ◽  
Nicole P. Sandhu ◽  
Mark Schuchard ◽  
M. Subramaniam ◽  
Thomas C. Spelsberg
Keyword(s):  
Nuclear Matrix ◽  
Binding Sites ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors

scholarly journals Functional interaction of hybrid response elements with wild-type and mutant steroid hormone receptors.

1991 ◽  
Vol 11 (6) ◽  
pp. 3247-3258 ◽  
Author(s):  
M Truss ◽  
G Chalepakis ◽  
E P Slater ◽  
S Mader ◽  
M Beato
Keyword(s):  
Glucocorticoid Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Single Amino Acid ◽  
Wild Type ◽  
Binding Domains ◽  
Responsive Element

Steroid hormone receptors can be divided into two subfamilies according to the structure of their DNA binding domains and the nucleotide sequences which they recognize. The glucocorticoid receptor and the progesterone receptor (PR) recognize an imperfect palindrome (glucocorticoid responsive element/progesterone responsive element [GRE/PRE]) with the conserved half-sequence TGTYCY, whereas the estrogen receptor (ER) recognizes a palindrome (estrogen responsive element) with the half-sequence TGACC. A series of symmetric and asymmetric variants of these hormone responsive elements (HREs) have been tested for receptor binding and for the ability to mediate induction in vivo. High-resolution analysis demonstrates that the overall number and distribution of contacts with the N-7 position of guanines and with the phosphate backbone of various HREs are quite similar for PR and ER. However, PR and glucocorticoid receptor, but not ER, are able to contact the 5'-methyl group of thymines found in position 3 of HREs, as shown by potassium permanganate interference. The ER mutant HE84, which contains a single amino acid exchange, Glu-203 to Gly, in the knuckle of ER, creates a promiscuous ER that is able to bind to GRE/PREs by contacting this thymine. Elements with the sequence GGTCAcagTGTYCT that represent hybrids between an estrogen response element and a GRE/PRE respond to estrogens, glucocorticoids, and progestins in vivo and bind all three wild-type receptors in vitro. These hybrid HREs could serve to confer promiscuous gene regulation.

scholarly journals The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2155
Author(s):  
Hiroki Ide ◽  
Hiroshi Miyamoto
Keyword(s):  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Tumor Development ◽  
Estrogen Receptor Α ◽  
Estrogen Receptor Β ◽  
Steroid Hormone Receptors

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.

scholarly journals A conserved mechanism of sirtuin signalling through steroid hormone receptors

2019 ◽  
Vol 39 (12) ◽  
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.

scholarly journals Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

2017 ◽  
Author(s):  
Jeffery M. Vahrenkamp ◽  
Chieh-Hsiang Yang ◽  
Adriana C. Rodriguez ◽  
Aliyah Almomen ◽  
Kristofer C. Berrett ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Endometrial Cancer ◽  
Glucocorticoid Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Estrogen Receptor Α ◽  
Steroid Hormone Receptors ◽  
Uterine Growth ◽  
Opposing Effects

SummarySteroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is significantly altered by estradiol with GR recruited to ER bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol, but with novel regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer.

Phasing the intranuclear organization of steroid hormone receptors

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.

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