scholarly journals Noncanonical Constitutive Androstane Receptor Signaling in Gene Regulation

2020 ◽  
Vol 21 (18) ◽  
pp. 6735
Author(s):  
Yuliya A. Pustylnyak ◽  
Lyudmila F. Gulyaeva ◽  
Vladimir O. Pustylnyak
Keyword(s):  
Cell Biology ◽  
Energy Homeostasis ◽  
Hormone Receptors ◽  
Target Genes ◽  
Constitutive Androstane Receptor ◽  
Steroid Hormone Receptors ◽  
Metabolizing Enzymes ◽  
Physiological Processes ◽  
Genes Encoding

The constitutive androstane receptor (CAR, NR1I3) is extremely important for the regulation of many physiological processes, especially xenobiotic (drug) metabolism and transporters. CAR differs from steroid hormone receptors in that it can be activated using structurally unrelated chemicals, both through direct ligand-binding and ligand-independent (indirect) mechanisms. By binding to specific responsive elements on DNA, CAR increases the expression of its target genes encoding drug-metabolizing enzymes and transporters. Therefore, CAR is mainly characterized as a ligand-dependent or ligand-independent transcription factor, and the induction of gene expression is considered the canonical mode of CAR action. Consistent with its central role in xenobiotic metabolism, CAR signaling includes a collection of mechanisms that are employed alongside the core transcriptional machinery of the receptor. These so-called noncanonical CAR pathways allow the receptor to coordinate the regulation of many aspects of cell biology. In this mini-review, we review noncanonical CAR signaling, paying special attention to the role of CAR in energy homeostasis and cell proliferation.

877 ROLE OF STEROID HORMONE RECEPTORS ON FORMATION AND PROGRESSION OF BLADDER CARCINOMA

2011 ◽  
Vol 185 (4S) ◽  
Author(s):  
Gholamreza Pourmand ◽  
Sepehr Salem ◽  
Abdolrasoul Mehrsai ◽  
Farid Kosari
Keyword(s):  
Bladder Carcinoma ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors

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 Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

2019 ◽  
Vol 37 (03) ◽  
pp. 131-140 ◽  
Author(s):  
Oline K. Rønnekleiv ◽  
Jian Qiu ◽  
Martin J. Kelly
Keyword(s):  
Energy Homeostasis ◽  
Hormone Receptors ◽  
Neuronal Excitability ◽  
Steroid Hormone Receptors ◽  
Synaptic Connections ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Energy States ◽  
Reproductive Activities ◽  
Metabolic Hormone

AbstractHypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.

scholarly journals Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2426
Author(s):  
Fabiana Oliviero ◽  
Céline Lukowicz ◽  
Badreddine Boussadia ◽  
Isabel Forner-Piquer ◽  
Jean-Marc Pascussi ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Physiological Stress ◽  
Neurovascular Unit ◽  
Constitutive Androstane Receptor ◽  
Functional Expression ◽  
Brain Diseases ◽  
Clear Understanding ◽  
Physiological Processes ◽  
Entry Points ◽  
Lipid Sensing

Xenobiotic nuclear receptors (NR) are intracellular players involved in an increasing number of physiological processes. Examined and characterized in peripheral organs where they govern metabolic, transport and detoxification mechanisms, accumulating data suggest a functional expression of specific NR at the neurovascular unit (NVU). Here, we focus on the Constitutive Androstane Receptor (CAR), expressed in detoxifying organs such as the liver, intestines and kidneys. By direct and indirect activation, CAR is implicated in hepatic detoxification of xenobiotics, environmental contaminants, and endogenous molecules (bilirubin, bile acids). Importantly, CAR participates in physiological stress adaptation responses, hormonal and energy homeostasis due to glucose and lipid sensing. We next analyze the emerging evidence supporting a role of CAR in NVU cells including the blood–brain barrier (BBB), a key vascular interface regulating communications between the brain and the periphery. We address the emerging concept of how CAR may regulate specific P450 cytochromes at the NVU and the associated relevance to brain diseases. A clear understanding of how CAR engages during pathological conditions could enable new mechanistic, and perhaps pharmacological, entry-points within a peripheral–brain axis.

scholarly journals Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

2019 ◽  
Author(s):  
Sharon Ann Barretto ◽  
Frederic Lasserre ◽  
Anne Fougerat ◽  
Lorraine Smith ◽  
Tiffany Fougeray ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Target Genes ◽  
Pregnane X Receptor ◽  
Alpha Activity ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Metabolizing Enzymes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Xenobiotic Metabolizing Enzymes ◽  
Triglyceride Accumulation

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes mostly xenobiotic metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

scholarly journals Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling

2021 ◽  
Vol 15 ◽  
Author(s):  
Jissele A. Verdinez ◽  
Julien A. Sebag
Keyword(s):  
Plasma Membrane ◽  
Energy Homeostasis ◽  
Reproductive Function ◽  
Receptor Trafficking ◽  
Membrane Localization ◽  
Accessory Protein ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Glycosylation Sites

Prokineticin receptors are GPCRs involved in several physiological processes including the regulation of energy homeostasis, nociception, and reproductive function. PKRs are inhibited by the endogenous accessory protein MRAP2 which prevents them from trafficking to the plasma membrane. Very little is known about the importance of post-translational modification of PKRs and their role in receptor trafficking and signaling. Here we identify 2 N-linked glycosylation sites within the N-terminal region of PKR2 and demonstrate that glycosylation of PKR2 at position 27 is important for its plasma membrane localization and signaling. Additionally, we show that glycosylation at position 7 results in a decrease in PKR2 signaling through Gαs without impairing Gαq/11 signaling.

Role of Androgen and Estrogen Receptors as Prognostic and Potential Predictive Markers of Ductal Carcinoma in Situ of the Breast

2015 ◽  
Vol 30 (4) ◽  
pp. 425-428 ◽  
Author(s):  
Maria Maddalena Tumedei ◽  
Rosella Silvestrini ◽  
Sara Ravaioli ◽  
Ilaria Massa ◽  
Roberta Maltoni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma In Situ ◽  
Carcinoma In Situ ◽  
Hormone Receptors ◽  
Ductal Carcinoma ◽  
Area Under The Curve ◽  
Steroid Hormone Receptors ◽  
Prognostic Indicators

Background Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Thus, the search for biomarkers capable of identifying DCIS lesions that may recur or progress to invasive cancer is ongoing. Although conventional steroid hormone receptors, cell proliferation and other important tumor markers have been extensively studied in invasive tumors, little is known about the role played by androgen receptors (ARs), widely expressed in breast cancer, in DCIS. Methods We performed a retrospective study in a series of 43 DCIS patients treated with quadrantectomy only and followed up for a period ranging from 5 to 13 years, to evaluate the prognostic relevance of conventional biomarkers (estrogen receptor [ER], progesterone receptor [PgR], Ki67, human epidermal growth factor receptor 2 [HER2]) and AR. Results Our findings showed that AR and ER were not independent prognostic variables and that an AR/ER ratio cutoff of 1.13 showed a sensitivity of 75% and a specificity of 94% in predicting in situ relapse or progression to the invasive phenotype. Moreover, while the variables considered singly showed area under the curve (AUC) values ranging from 0.52% to 0.77%, the AR/ER ratio reached a very high AUC (0.92%). Conclusions These preliminary results highlight the potentially important role of AR and ER and, in particular, of their ratio, as prognostic indicators of DCIS evolution.

Proliferative diseases of the uterus: clinical, immunological, and molecular aspects

2020 ◽  
Vol 19 (5) ◽  
pp. 13-21
Author(s):  
S.V. Shramko ◽  
◽  
L.F. Gulyaeva ◽  
V.N. Zorina ◽  
T.V. Tretyakova ◽  
...  
Keyword(s):  
Estrogen Receptors ◽  
Hormone Receptors ◽  
Acute Phase Proteins ◽  
Uterine Fibroids ◽  
Progesterone Receptors ◽  
Serum Levels ◽  
Steroid Hormone Receptors ◽  
Sex Steroid Hormone ◽  
Expression Of Genes ◽  
Genes Encoding

Objective. To perform comparative analysis of clinical data, serum levels of acute-phase proteins, cytokines, steroid hormones, and expression of genes encoding sex hormone receptors in tissues of patients with proliferative diseases of the uterus. Patients and methods. We analyzed clinical data of 349 patients with various proliferative diseases of the uterus. We also evaluated their serum levels of α2-macroglobulin, pregnancy-associated α2-glycoprotein, their immunocomplexes with IgG, lactoferrin, VEGF, IL-6, TNFa, IL-8, and sex hormones. Uterine tissue samples were tested for the expression of genes encoding estrogen receptors α and β (ЕRα, ЕRβ) and progesterone receptors (PGR). Data analysis was performed using the statistical packages of SAS 9.4, STATISTICA12, and IBM-SPSS Statistics 22. Results. The changes in the level of acute-phase proteins indicated inflammation. In isolated uterine fibroids, expression of genes encoding progesterone receptors prevailed, whereas in isolated adenomyosis, expression of genes encoding estrogen receptors prevailed. Patients with both uterine fibroids and adenomyosis demonstrated similar levels of expression of genes encoding sex steroid hormone receptors. Tissues of uterine leiomyosarcoma were characterized by downregulated expression of genes encoding sex steroid hormone receptors. Conclusion. Upregulation of genes encoding progesterone receptors in isolated uterine fibroids confirms that therapy with progesterone receptor blockers is appropriate in this case. The predominance of expression of genes encoding estrogen receptors in isolated adenomyosis indicates local hyperestrogenism, justifying the use of progestogens and antiestrogens. Equal expression of genes encoding estrogen and progesterone receptors in patients with combined disease, as wells as high frequency of inflammatory changes in tissues and increased serum levels of inflammatory markers, proves the need for antiinflammatory therapy. Key words: adenomyosis, inflammation, steroid receptor genes, leiomyosarcoma, uterine fibroids, gene expression

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