scholarly journals Steroid hormone receptors and dietary ligands: a selected review

2002 ◽  
Vol 61 (1) ◽  
pp. 105-122 ◽  
Author(s):  
Miriam N. Jacobs* ◽  
David F. V. Lewis
Keyword(s):  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Pregnane X Receptor ◽  
Steroid Hormone Receptors ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Dietary Intakes ◽  
Food Contaminants ◽  
Exogenous Compounds

Members of the nuclear steroid hormone superfamily mediate essential physiological functions. Steroid hormone receptors (SHR) act directly on DNA, regulate the synthesis of their target genes and are usually activated by ligand binding. Both endogenous and exogenous compounds and their metabolites may act as activators of SHR and disruptors of endocrine, cellular and lipid homeostasis. The endogenous ligands are generally steroids such as 17β-oestradiol, androgens, progesterone and pregnenolone. The exogenous compounds are usually delivered through the diet and include non-steroidal ligands. Examples of such ligands include isoflavanoids or phyto-oestrogens, and food contaminants such as exogenous oestrogens from hormone-treated cattle, pesticides, polychlorinated biphenyls and plasticisers. Certain drugs are also ligands; so nuclear receptors are also important drug targets for intervention in disease processes. The present review summarises recent reports on ligand-activated SHR that describe the selective regulation of a tightly-controlled cross-talking network involving exchange of ligands, and the control of major classes of cytochrome P450 (CYP) isoforms which metabolise many bioactive exogenous compounds. Many CYP have broad substrate activity and appear to be integrated into a coordinated metabolic pathway, such that whilst some receptors are ligand specific, other sensors may have a broader specificity and low ligand affinity to monitor aggregate levels of inducers. They can then trigger production of metabolising enzymes to defend against possible toxic nutrients and xenobiotic compounds. The influence of dietary intakes of nutrients and non-nutrients on the human oestrogen receptors (α and β), the aryl hydrocarbon receptor, the pregnane X receptor, the constitutive androstane receptor, and the peroxisome proliferator-activated receptors (α and γ), can be examined by utilising computer-generated molecular models of the ligand–receptor interaction, based on information generated from crystallographic data and sequence homology. In relation to experimental and observed data, molecular modelling can provide a scientifically sound perspective on the potential risk and benefits to human health from dietary exposure to hormone-mimicking chemicals, providing a useful tool in drug development and in a situation of considerable public concern.

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 Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2

1998 ◽  
Vol 18 (10) ◽  
pp. 6001-6013 ◽  
Author(s):  
Jörg Leers ◽  
Eckardt Treuter ◽  
Jan-Åke Gustafsson
Keyword(s):  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Nuclear Hormone Receptors ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Interaction Domain ◽  
Interacting Protein ◽  
Necessary And Sufficient ◽  
Dependent Interaction

ABSTRACT Nuclear hormone receptors exert transcriptional activation of target genes upon hormone induction via interactions with the basal transcription machinery. This interaction is mediated by cofactors which physically bind to receptors, thereby acting as coactivators or corepressors leading to activation or repression, respectively. Here we report the screening for and cloning of a peroxisome proliferator receptor-interacting protein, the rat homolog of TIF2. By sequence comparison with the related coactivator SRC-1, we identified three short conserved motifs (NR boxes) in both proteins which are the putative binding sites of TIF2 to nuclear hormone receptors. We demonstrate here by generation of amino acid exchanges within the NR boxes that all three boxes located in the receptor interaction domain of TIF2 are necessary and sufficient for interaction. The three boxes individually can bind to hormone receptors but display preferences in binding for certain receptors. In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors. Finally, we demonstrate cooperative binding of two TIF2 molecules to a heterodimeric nuclear receptor complex even in the presence of only one cognate ligand, indicating an allosteric effect on the heterodimeric partner upon coactivator binding.

The androgen receptor DNA-binding domain determines androgen selectivity of transcriptional response

2006 ◽  
Vol 34 (6) ◽  
pp. 1089-1094 ◽  
Author(s):  
G. Verrijdt ◽  
T. Tanner ◽  
U. Moehren ◽  
L. Callewaert ◽  
A. Haelens ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Dna Binding ◽  
Cellular Response ◽  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Prostate Gland ◽  
Steroid Hormone Receptors ◽  
Binding Motif

The AR (androgen receptor) is a hormone-dependent transcription factor that translates circulating androgen hormone levels into a physiological cellular response by directly regulating the expression of its target genes. It is the key molecule in e.g. the development and maintenance of the male sexual characteristics, spermatocyte production and prostate gland development and growth. It is also a major factor in the onset and maintenance of prostate cancer and a first target for pharmaceutical action against the further proliferation of prostate cancer cells. The AR is a member of the steroid hormone receptors, a group of steroid-inducible transcription factors sharing an identical consensus DNA-binding motif. The problem of how specificity in gene activation is achieved among the different members of this nuclear receptor subfamily is still unclear. In this report, we describe our investigations on how the AR can specifically activate its target genes, while the other steroid hormone receptors do not, despite having the same consensus monomeric DNA-binding motif. In this respect, we describe how the AR interacts with a newly identified class of steroid-response elements to which only the AR and not, for example, the glucocorticoid receptor can bind.

scholarly journals Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Hiroki Ide ◽  
Hiroshi Miyamoto
Keyword(s):  
Hormone Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Critical Role ◽  
Steroid Hormone Receptors ◽  
Steroid Hormone Receptor ◽  
Cancer Tissue ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Tissue Specimens

There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

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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