Human disorders caused by nuclear receptor gene mutations

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1785-1796 ◽  
Author(s):  
J. C. Achermann ◽  
J. L. Jameson
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Gene ◽  
Critical Role ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Orphan Nuclear Receptors ◽  
Naturally Occurring ◽  
Inactivating Mutations

The identification of naturally occurring nuclear receptor mutations highlights the critical role that many of these transcription factors play in human endocrine development and function. Inactivating mutations in the ligand-dependent nuclear receptors (TRβ, VDR, ERα, GR, MR, AR) are well characterized in patients with conditions such as androgen insensitivity syndrome (AIS) and vitamin D resistance. On the other hand, mutations in TRβ act in a dominant negative manner to cause hormone resistance. Inactivating mutations in orphan nuclear receptors have also been identified (PPARγ2, HNF4α, PNR, NURR1, SF1, DAX1, SHP) and reveal important developmental and metabolic functions for this group of receptors with previously elusive physiologic roles. In addition to loss of function mutations, receptor activation can result from mutations that confer constitutive activity or altered ligand responsiveness to the receptor (MR, AR), or from genetic duplication (DAX1) or the expression of fusion proteins (RARA, PPARγ1). Together, these naturally occurring mutations provide fascinating insight into key structural and functional receptor domains to reveal the diverse role nuclear receptors play in human biology.

scholarly journals ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

2017 ◽  
Vol 214 (3) ◽  
pp. 669-680 ◽  
Author(s):  
J.J. Lyons ◽  
Y. Liu ◽  
C.A. Ma ◽  
X. Yu ◽  
M.P. O’Connell ◽  
...  
Keyword(s):  
Allergic Diseases ◽  
Foxp3 Expression ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Naturally Occurring ◽  
Pathway Activation

Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-β activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-β signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut) have evidence of deregulated TGF-β signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3–ERBIN–SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-β. In turn, cell-intrinsic deregulation of TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-β pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

scholarly journals c-Jun N-Terminal Kinase Activation of Activator Protein-1 Underlies Homologous Regulation of the Gonadotropin-Releasing Hormone Receptor Gene in αT3-1 Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 839-849 ◽  
Author(s):  
Buffy S. Ellsworth ◽  
Brett R. White ◽  
Ann T. Burns ◽  
Brian D. Cherrington ◽  
Annette M. Otis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cell Model ◽  
Receptor Gene ◽  
Critical Role ◽  
Dominant Negative ◽  
Activator Protein 1 ◽  
Activator Protein

Reproductive function is dependent on the interaction between GnRH and its cognate receptor found on gonadotrope cells of the anterior pituitary gland. GnRH activation of the GnRH receptor (GnRHR) is a potent stimulus for increased expression of multiple genes including the gene encoding the GnRHR itself. Thus, homologous regulation of the GnRHR is an important mechanism underlying gonadotrope sensitivity to GnRH. Previously, we have found that GnRH induction of GnRHR gene expression in αT3-1 cells is partially mediated by protein kinase C activation of a canonical activator protein-1 (AP-1) element. In contrast, protein kinase A and a cAMP response element-like element have been implicated in mediating the GnRH response of the GnRHR gene using a heterologous cell model (GGH3). Herein we find that selective removal of the canonical AP-1 site leads to a loss of GnRH regulation of the GnRHR promoter in transgenic mice. Thus, an intact AP-1 element is necessary for GnRH responsiveness of the GnRHR gene both in vitro and in vivo. Based on in vitro analyses, GnRH appeared to enhance the interaction of JunD, FosB, and c-Fos at the GnRHR AP-1 element. Although enhanced binding of cFos reflected an increase in gene expression, GnRH appeared to regulate both FosB and JunD at a posttranslational level. Neither overexpression of a constitutively active Raf-kinase nor pharmacological blockade of GnRH-induced ERK activation eliminated the GnRH response of the GnRHR promoter. GnRH responsiveness was, however, lost in αT3-1 cells that stably express a dominant-negative c-Jun N-terminal kinase (JNK) kinase, suggesting a critical role for JNK in mediating GnRH regulation of the GnRHR gene. Consistent with this possibility, we find that the ability of forskolin and membrane-permeable forms of cAMP to inhibit the GnRH response of the GnRHR promoter is associated with a loss of both JNK activation and GnRH-mediated recruitment of the primary AP-1-binding components.

scholarly journals Nuclear receptor phosphorylation in xenobiotic signal transduction

2020 ◽  
Vol 295 (45) ◽  
pp. 15210-15225 ◽  
Author(s):  
Masahiko Negishi ◽  
Kaoru Kobayashi ◽  
Tsutomu Sakuma ◽  
Tatsuya Sueyoshi
Keyword(s):  
Dna Binding ◽  
Cell Signaling ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Binding Domain ◽  
Activation Mechanism ◽  
Dna Binding Domain ◽  
Phosphorylation Motif

Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, which does not bind CAR directly, presented an alternative research avenue for an indirect ligand-mediated nuclear receptor activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized by xenobiotics to elicit cell signaling. First, the review presents how PB activates CAR (and other nuclear receptors) through a conserved phosphorylation motif located between two zinc fingers within its DNA-binding domain. PB-regulated phosphorylation at this motif enables nuclear receptors to form communication networks, integrating their functions. Next, the review discusses xenobiotic-induced PXR activation in the absence of the conserved DNA-binding domain phosphorylation motif. In this case, phosphorylation occurs at a motif located within the ligand-binding domain to transduce cell signaling that regulates hepatic energy metabolism. Finally, the review delves into the implications of xenobiotic-induced signaling through phosphorylation in disease development and progression.

scholarly journals Drug-Regulated Expression of Plasmodium falciparum P-Glycoprotein Homologue 1: a Putative Role for Nuclear Receptors

2008 ◽  
Vol 52 (4) ◽  
pp. 1438-1445 ◽  
Author(s):  
David J. Johnson ◽  
Andrew Owen ◽  
Nick Plant ◽  
Patrick G. Bray ◽  
Stephen A. Ward
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Mechanism ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Drug Exposure ◽  
Receptor Gene ◽  
Acquired Resistance ◽  
Proximal Promoter ◽  
Whole Genome Analysis ◽  
P Glycoprotein

ABSTRACT Acquired resistance to therapeutic agents is a major clinical concern in the prevention/treatment of malaria. The parasite has developed resistance to specific drugs through two mechanisms: mutations in target proteins such as dihydrofolate reductase and the bc1 complex for antifolates and nathoquinones, respectively, and alterations in predicted parasite transporter molecules such as P-glycoprotein homologue 1 (Pgh1) and Plasmodium falciparum CRT (PfCRT). Alterations in the expression of Pgh1 have been associated with modified susceptibility to a range of unrelated drugs. The molecular mechanism(s) that is responsible for this phenotype is unknown. We have shown previously (A. M. Ndifor, R. E. Howells, P. G. Bray, J. L. Ngu, and S. A. Ward, Antimicrob. Agents Chemother. 37:1318-1323, 2003) that the anticonvulsant phenobarbitone (PB) can induce reduced susceptibility to chloroquine (CQ) in P. falciparum, and in the current study, we provide the first evidence for a molecular mechanism underlying this phenomenon. We demonstrate that pretreatment with PB can elicit decreased susceptibility to CQ in both CQ-resistant and CQ-sensitive parasite lines and that this is associated with the increased expression of the drug transporter Pgh1 but not PfCRT. Furthermore, we have investigated the proximal promoter regions from both pfmdr1 and pfcrt and identified a number of putative binding sites for nuclear receptors with sequence similarities to regions known to be activated by PB in mammals. Whole-genome analysis has revealed a putative nuclear receptor gene, providing the first evidence that nuclear receptor-mediated responses to drug exposure may be a mechanism of gene regulation in P. falciparum.

scholarly journals Minireview: Genomics Versus Orphan Nuclear Receptors—A Half-Time Report

2002 ◽  
Vol 16 (6) ◽  
pp. 1135-1144
Author(s):  
Timothy M. Willson ◽  
John T. Moore
Keyword(s):  
Nuclear Receptors ◽  
Drug Targets ◽  
Hormone Receptors ◽  
Receptor Gene ◽  
Orphan Nuclear Receptors ◽  
Orphan Receptors ◽  
Genomic Technologies ◽  
Full Complement ◽  
And Function ◽  
The Impact

Abstract Following the successful cloning of the orphan nuclear receptors during the 1990s we entered the 21st century with knowledge of the full complement of human nuclear receptors. Many of these proteins are ligand-activated transcription factors that act as the cognate receptors for steroid, retinoid, and thyroid hormones. In addition to these well characterized endocrine hormone receptors, there are a large number of orphan receptors of which less is known about the nature and function of their ligands. The task of deciphering the physiological function of these orphan receptors has been aided by a new generation of genomic technologies. Through application of chemical, structural, and functional genomics, several orphan nuclear receptors have emerged as pharmaceutical drug targets for the treatment of important human diseases. The significant progress that has been made in the functional analysis of more than half of the nuclear receptor gene family provides an opportunity to review the impact of genomics in this endeavor.

A critical role for PI 3-kinase in cytokine-induced Fcα-receptor activation

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2037-2043 ◽  
Author(s):  
Madelon Bracke ◽  
Evert Nijhuis ◽  
Jan-Willem J. Lammers ◽  
Paul J. Coffer ◽  
Leo Koenderman
Keyword(s):  
Ligand Binding ◽  
Signaling Pathways ◽  
Critical Role ◽  
Immunoglobulin A ◽  
Fc Receptors ◽  
Receptor Activation ◽  
Molecular Techniques ◽  
Dominant Negative ◽  
Receptor Modulation ◽  
Inside Out

Abstract Fc-receptors, such as FcR and FcγRII, play an important role in leukocyte activation, and rapid modulation of ligand binding (“activation”) is critical for receptor regulation. We have previously demonstrated that ligand binding to Fc-receptors on human eosinophils is dependent on cytokine stimulation. Utilization of pharmacological inhibitors provided evidence that the phenomenon of interleukin (IL)-5 induced immunoglobulin A (IgA) binding to human eosinophils requires activation of phosphatidylinositol 3-kinase (PI3K). However, eosinophils are refractory to manipulation by molecular techniques such as DNA transfection or viral infection. Here we utilize an IL-3 dependent pre-B cell line to investigate the molecular mechanism of cytokine-mediated ligand binding to FcR. In this system, IgA binding is dependent on IL-3, similarly to the requirement for IL-5 of eosinophils. We show that IL-3-mediated activation of FcR (CD89) requires the activation of PI3K, independent of p21ras activation. Co-expression of dominant negative (▵p85) and active (p110_K227E) forms of PI3K demonstrate that the affinity switch regulating FcR activation requires PI3K. Moreover, overexpression of PI3K is both necessary and sufficient for activation of FcR. Furthermore, we show that IL-3/IL-5/GM-CSF induced inside-out signaling pathways activating FcR require the involvement of protein kinase C downstream of PI3K. Finally, we show that these inside-out signaling pathways responsible for Fc-receptor modulation require CD89, independent of its association with the FcRγ chain.

scholarly journals Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype

2015 ◽  
Vol 308 (6) ◽  
pp. F627-F638 ◽  
Author(s):  
Merle L. Gilbert ◽  
Linghai Yang ◽  
Thomas Su ◽  
G. Stanley McKnight
Keyword(s):  
Diabetes Insipidus ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Critical Role ◽  
Physiological Role ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Water Excretion ◽  
Protein Levels

PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 ( Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIαB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIαB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIαB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIαB-expressing mice, but AQP2 protein levels were still reduced in RIαB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus.

scholarly journals Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

2004 ◽  
Vol 25 (1) ◽  
pp. 45-71 ◽  
Author(s):  
Carolyn L. Smith ◽  
Bert W. O’Malley
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Critical Role ◽  
Dependent Manner ◽  
Nuclear Receptor Superfamily ◽  
Binding Domains ◽  
Receptor Modulator ◽  
Cellular Environment ◽  
Receptor Modulators

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

scholarly journals Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis

2009 ◽  
Vol 29 (7) ◽  
pp. 1719-1734 ◽  
Author(s):  
Bin Xu ◽  
Wei-Hsiung Yang ◽  
Isabelle Gerin ◽  
Chang-Deng Hu ◽  
Gary D. Hammer ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Regulatory Protein ◽  
Steroid Receptor ◽  
Gene Products ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Steroidogenic Factor 1 ◽  
Naturally Occurring ◽  
Steroidogenic Acute Regulatory

ABSTRACT The nuclear receptor steroidogenic factor 1 (SF-1) is essential for adrenal development and steroidogenesis. The atypical orphan nuclear receptor Dax-1 binds to SF-1 and represses SF-1 target genes. Paradoxically, however, loss-of-function mutations of Dax-1 also cause adrenal hypoplasia, suggesting that Dax-1 may function as an SF-1 coactivator under some circumstances. Indeed, we found that Dax-1 can function as a dosage-dependent SF-1 coactivator. Both SF-1 and Dax-1 bind to steroid receptor RNA activator (SRA), a coactivator that functions as an RNA. The coactivator TIF2 also associates with Dax-1 and synergistically coactivates SF-1 target gene transcription. A naturally occurring Dax-1 mutation inhibits this transactivation, and the mutant Dax-1-TIF2 complex mislocalizes in living cells. Coactivation by Dax-1 is abolished by SRA knockdown. The expression of the steroidogenic gene products steroidogenic acute regulatory protein (StAR) and melanocortin 2 receptor is reduced in adrenal Y1 cells following the knockdown of endogenous SRA. Similarly, the knockdown of endogenous Dax-1 downregulates the expression of the steroidogenic gene products CYP11A1 and StAR in both H295R adrenal and MA-10 Leydig cells. These findings reveal novel functions of SRA and Dax-1 in steroidogenesis and adrenal biology.

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