scholarly journals Regulation of CAR and PXR Expression in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2395
Author(s):  
Martine Daujat-Chavanieu ◽  
Sabine Gerbal-Chaloin
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptor ◽  
Current Knowledge ◽  
Constitutive Androstane Receptor ◽  
Adult Life ◽  
Pregnane X Receptor ◽  
Regulatory Mechanisms ◽  
Nuclear Receptor Superfamily ◽  
Pathological Conditions ◽  
Health And Disease

Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.

scholarly journals The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1192 ◽  
Author(s):  
Philip Marx-Stoelting ◽  
Constanze Knebel ◽  
Albert Braeuning
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Liver Tumors ◽  
Current Knowledge ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Azole Fungicides

Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.

scholarly journals Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1852 ◽  
Author(s):  
Baylee A. Porter ◽  
Maria A. Ortiz ◽  
Gennady Bratslavsky ◽  
Leszek Kotula
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Cell Permeability ◽  
Cancer Therapies ◽  
Functional Difference ◽  
Nuclear Receptor Superfamily ◽  
Functional Regulation ◽  
And Function

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

scholarly journals Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2295
Author(s):  
Bradley A. Creamer ◽  
Shelly N. B. Sloan ◽  
Jennifer F. Dennis ◽  
Robert Rogers ◽  
Sidney Spencer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Breast Tissue ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Pregnane X Receptor ◽  
Chemotherapeutic Agents ◽  
Bile Acid Metabolism ◽  
Cytochrome P450 Enzymes ◽  
Cellular Detoxification

Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism. While PXR clearly has important regulatory roles in the liver and gastrointestinal tract, this nuclear receptor also has biological functions in breast tissue. In this review, we highlight current knowledge of PXR’s role in mammary tumor carcinogenesis. The elevated level of PXR expression in cancerous breast tissue suggests a likely interface between aberrant cell division and xeno-protection in cancer cells. Moreover, PXR itself exerts positive effect on the cell cycle, thereby predisposing tumor cells to unchecked proliferation. Activation of PXR also plays a key role in regulating apoptosis, as well as in acquired resistance to chemotherapeutic agents. The repressive role of PXR in regulating inflammatory mediators along with the existence of genetic polymorphisms within the sequence of the PXR gene may predispose individuals to developing breast cancer. Further investigations into the role that PXR plays in driving tumorigenesis are needed.

scholarly journals The Nuclear Receptor PXR in Chronic Liver Disease

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 61
Author(s):  
Katia Sayaf ◽  
Ilaria Zanotto ◽  
Francesco Paolo Russo ◽  
Daniela Gabbia ◽  
Sara De Martin
Keyword(s):  
Nuclear Receptor ◽  
Liver Diseases ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Chronic Liver ◽  
Cytochrome P450 3A4 ◽  
Chronic Liver Diseases ◽  
Metabolizing Enzymes ◽  
P Glycoprotein ◽  
And Function

Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

scholarly journals The NR3B Subgroup: An Overrview

2007 ◽  
Vol 5 (1) ◽  
pp. nrs.05009 ◽  
Author(s):  
Annie M. Tremblay ◽  
Vincent Giguère
Keyword(s):  
Transcription Factors ◽  
Functional Genomics ◽  
Nuclear Receptor ◽  
Mode Of Action ◽  
Current Understanding ◽  
Biological Functions ◽  
Orphan Receptors ◽  
Nuclear Receptor Superfamily ◽  
Natural Ligand ◽  
Biochemical Genetic

Members of the NR3B group of the nuclear receptor superfamily, known as the estrogen-related receptors (ERRs), were the first orphan receptors to be identified two decades ago. Despite the fact that a natural ligand has yet to be associated with the ERRs, considerable knowledge about their mode of action and biological functions has emerged through extensive biochemical, genetic and functional genomics studies. This review describes our current understanding of how the ERRs work as transcription factors and as such, how they control diverse developmental and physiological programs.

scholarly journals DNMTs and Impact of CpG Content, Transcription Factors, Consensus Motifs, lncRNAs, and Histone Marks on DNA Methylation

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1336 ◽  
Author(s):  
Jaqueline Loaeza-Loaeza ◽  
Adriana S. Beltran ◽  
Daniel Hernández-Sotelo
Keyword(s):  
Dna Methylation ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Histone Marks ◽  
Spatiotemporal Regulation ◽  
Genome Wide ◽  
Health And Disease ◽  
Methylation Patterns

DNA methyltransferases (DNMTs) play an essential role in DNA methylation and transcriptional regulation in the genome. DNMTs, along with other poorly studied elements, modulate the dynamic DNA methylation patterns of embryonic and adult cells. We summarize the current knowledge on the molecular mechanism of DNMTs’ functional targeting to maintain genome-wide DNA methylation patterns. We focus on DNMTs’ intrinsic characteristics, transcriptional regulation, and post-transcriptional modifications. Furthermore, we focus special attention on the DNMTs’ specificity for target sites, including key cis-regulatory factors such as CpG content, common motifs, transcription factors (TF) binding sites, lncRNAs, and histone marks to regulate DNA methylation. We also review how complexes of DNMTs/TFs or DNMTs/lncRNAs are involved in DNA methylation in specific genome regions. Understanding these processes is essential because the spatiotemporal regulation of DNA methylation modulates gene expression in health and disease.

scholarly journals Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Cristiana Pistono ◽  
Nea Bister ◽  
Iveta Stanová ◽  
Tarja Malm
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Extracellular Vesicles ◽  
Glial Cells ◽  
Current Knowledge ◽  
Physiological State ◽  
General Term ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Health And Disease

Glial cells are crucial for the maintenance of correct neuronal functionality in a physiological state and intervene to restore the equilibrium when environmental or pathological conditions challenge central nervous system homeostasis. The communication between glial cells and neurons is essential and extracellular vesicles (EVs) take part in this function by transporting a plethora of molecules with the capacity to influence the function of the recipient cells. EVs, including exosomes and microvesicles, are a heterogeneous group of biogenetically distinct double membrane-enclosed vesicles. Once released from the cell, these two types of vesicles are difficult to discern, thus we will call them with the general term of EVs. This review is focused on the EVs secreted by astrocytes, oligodendrocytes and microglia, aiming to shed light on their influence on neurons and on the overall homeostasis of the central nervous system functions. We collect evidence on neuroprotective and homeostatic effects of glial EVs, including neuronal plasticity. On the other hand, current knowledge of the detrimental effects of the EVs in pathological conditions is addressed. Finally, we propose directions for future studies and we evaluate the potential of EVs as a therapeutic treatment for neurological disorders.

scholarly journals Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

2019 ◽  
Author(s):  
Baylee Porter ◽  
Maria A. Ortiz ◽  
Gennady Bratslavsky ◽  
Leszek Kotula
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Cell Permeability ◽  
Cancer Therapies ◽  
Functional Difference ◽  
Nuclear Receptor Superfamily ◽  
Functional Regulation ◽  
And Function

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible than others to develop due to ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

The evolution of the nuclear receptor superfamily

2004 ◽  
Vol 40 ◽  
pp. 11-26 ◽  
Author(s):  
Héctor Escriva ◽  
Stéphanie Bertrand ◽  
Vincent Laudet
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Evolutionary History ◽  
Hormone Receptors ◽  
Nuclear Receptor Superfamily ◽  
Complete Genomes ◽  
High Degree ◽  
Animal Genomes

Nuclear receptors form a superfamily of ligand-activated transcription factors implicated in various physiological functions from development to homoeostasis. Nuclear receptors share a common evolutionary history revealed by their conserved structure and by their high degree of sequence conservation. Here we review the latest advances on the evolution of nuclear receptors by addressing the following questions. What is known about the appearance and diversification of nuclear hormone receptors? How did their different functional characteristics evolve? What can we infer from the analysis of complete genomes? In summary, the study of the evolution of nuclear receptors will be very important not only for understanding their functions in vivo but also for obtaining insights into the evolution of animal genomes as a whole.

Sign in / Sign up

Export Citation Format

Share Document