Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis.


:The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse chemicals. To examine the mechanisms responsible for the promiscuity in AhR ligand binding, we determined the effects of mutations within the AhR ligand-binding domain (LBD) on the activity of diverse AhR ligands. Site-directed mutagenesis identified Ile319 of the mouse AhR and, to a lesser extent, Phe318 as residues involved in ligand-selective modulation of AhR transformation using a panel of 12 AhR ligands. These ligands could be categorized into four distinct structurally related groups based on their ability to activate AhR mutants at position 319 in vitro. The mutation I319K was selectively activated by FICZ and not by other examined ligands in vitro and in cell culture. F318L and F318A mutations resulted in the conversion of AhR agonists β-naphthoflavone and 3-methylcholanthrene, respectively, into partial agonists/antagonists. Hsp90 binding to the AhR was decreased with several mutations and was inversely correlated with AhR ligand-binding promiscuity. Together, these data define overlapping amino acid residues within the AhR LBD involved in the selectivity of ligand binding, the agonist or antagonist mode of ligand binding, and hsp90 binding and provide insights into the ligand diversity of AhR activators.


Mol Cell Biol


Soshilov AA,Denison MS




Has Abstract


2014-05-01 00:00:00














  • MDS1, a dosage suppressor of an mck1 mutant, encodes a putative yeast homolog of glycogen synthase kinase 3.

    abstract::The yeast gene MCK1 encodes a serine/threonine protein kinase that is thought to function in regulating kinetochore activity and entry into meiosis. Disruption of MCK1 confers a cold-sensitive phenotype, a temperature-sensitive phenotype, and sensitivity to the microtubule-destabilizing drug benomyl and leads to loss ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Puziss JW,Hardy TA,Johnson RB,Roach PJ,Hieter P

    更新日期:1994-01-01 00:00:00

  • Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment.

    abstract::Histone H3 lysine 9 (H3-K9) methylation has been shown to correlate with transcriptional repression and serve as a specific binding site for heterochromatin protein 1 (HP1). In this study, we investigated the relationship between H3-K9 methylation, transcriptional repression, and HP1 recruitment by comparing the effec...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Stewart MD,Li J,Wong J

    更新日期:2005-04-01 00:00:00

  • Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

    abstract::DNA mismatch repair maintains genomic stability by detecting and correcting mispaired DNA sequences and by signaling cell death when DNA repair fails. The mechanism by which mismatch repair coordinates DNA damage and repair with cell survival or death is not understood, but it suggests the need for regulation. Since t...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wu X,Platt JL,Cascalho M

    更新日期:2003-05-01 00:00:00

  • Signaling in the yeast pheromone response pathway: specific and high-affinity interaction of the mitogen-activated protein (MAP) kinases Kss1 and Fus3 with the upstream MAP kinase kinase Ste7.

    abstract::Kss1 and Fus3 are mitogen-activated protein kinases (MAPKs or ERKs), and Ste7 is their activating MAPK/ERK kinase (MEK), in the pheromone response pathway of Saccharomyces cerevisiae. To investigate the potential role of specific interactions between these enzymes during signaling, their ability to associate with each...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bardwell L,Cook JG,Chang EC,Cairns BR,Thorner J

    更新日期:1996-07-01 00:00:00

  • Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1.

    abstract::The Ran binding protein RanBP1 is localized to the cytosol of interphase cells. A leucine-rich nuclear export signal (NES) near the C terminus of RanBP1 is essential to maintain this distribution. We now show that RanBP1 accumulates in nuclei of cells treated with the export inhibitor, leptomycin B, and collapse of th...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Plafker K,Macara IG

    更新日期:2000-05-01 00:00:00

  • RNA polymerase II carboxy-terminal domain phosphorylation is required for cotranscriptional pre-mRNA splicing and 3'-end formation.

    abstract::We investigated the role of RNA polymerase II (pol II) carboxy-terminal domain (CTD) phosphorylation in pre-mRNA processing coupled and uncoupled from transcription in Xenopus oocytes. Inhibition of CTD phosphorylation by the kinase inhibitors 5,6-dichloro-1beta-D-ribofuranosyl-benzimidazole and H8 blocked transcripti...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bird G,Zorio DA,Bentley DL

    更新日期:2004-10-01 00:00:00

  • Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.

    abstract::We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inh...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Mayer BJ,Baltimore D

    更新日期:1994-05-01 00:00:00

  • Redundancy of the two dicer genes in transgene-induced posttranscriptional gene silencing in Neurospora crassa.

    abstract::RNA interference (RNAi) in animals, cosuppression in plants, and quelling in fungi are homology-dependent gene silencing mechanisms in which the introduction of either double-stranded RNA (dsRNA) or transgenes induces sequence-specific mRNA degradation. These phenomena share a common genetic and mechanistic basis. The...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Catalanotto C,Pallotta M,ReFalo P,Sachs MS,Vayssie L,Macino G,Cogoni C

    更新日期:2004-03-01 00:00:00

  • Unraveling the intricate organization of mammalian mitochondrial presequence translocases: existence of multiple translocases for maintenance of mitochondrial function.

    abstract::Mitochondria are indispensable organelles implicated in multiple aspects of cellular processes, including tumorigenesis. Heat shock proteins play a critical regulatory role in accurately delivering the nucleus-encoded proteins through membrane-bound presequence translocase (Tim23 complex) machinery. Although altered e...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Sinha D,Srivastava S,Krishna L,D'Silva P

    更新日期:2014-05-01 00:00:00

  • When Long Noncoding Becomes Protein Coding.

    abstract::Recent advancements in genetic and proteomic technologies have revealed that more of the genome encodes proteins than originally thought possible. Specifically, some putative long noncoding RNAs (lncRNAs) have been misannotated as noncoding. Numerous lncRNAs have been found to contain short open reading frames (sORFs)...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章,评审


    authors: Hartford CCR,Lal A

    更新日期:2020-02-27 00:00:00

  • The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

    abstract::The biological response to progesterone is mediated by two distinct forms of the human progesterone receptor (hPR-A and hPR-B). In most cell contexts, hPR-B functions as a transcriptional activator of progesterone-responsive genes, whereas hPR-A functions as a transcriptional inhibitor of all steroid hormone receptors...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wen DX,Xu YF,Mais DE,Goldman ME,McDonnell DP

    更新日期:1994-12-01 00:00:00

  • Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells.

    abstract::Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Miyagawa Y,Okita H,Nakaijima H,Horiuchi Y,Sato B,Taguchi T,Toyoda M,Katagiri YU,Fujimoto J,Hata J,Umezawa A,Kiyokawa N

    更新日期:2008-04-01 00:00:00

  • The granulocyte-macrophage colony-stimulating factor promoter cis-acting element CLE0 mediates induction signals in T cells and is recognized by factors related to AP1 and NFAT.

    abstract::Expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in T cells is activated by the combination of phorbol ester (phorbol myristate acetate) and calcium ionophore (A23187), which mimic antigen stimulation through the T-cell receptor. We have previously shown that a fragment containing bp -9...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Masuda ES,Tokumitsu H,Tsuboi A,Shlomai J,Hung P,Arai K,Arai N

    更新日期:1993-12-01 00:00:00

  • Conserved pattern of antisense overlapping transcription in the homologous human ERCC-1 and yeast RAD10 DNA repair gene regions.

    abstract::We report that the genes for the homologous Saccharomyces cerevisiae RAD10 and human ERCC-1 DNA excision repair proteins harbor overlapping antisense transcription units in their 3' regions. Since naturally occurring antisense transcription is rare in S. cerevisiae and humans (this is the first example in human cells)...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: van Duin M,van Den Tol J,Hoeijmakers JH,Bootsma D,Rupp IP,Reynolds P,Prakash L,Prakash S

    更新日期:1989-04-01 00:00:00

  • The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo.

    abstract::p36, a major in vivo substrate of protein-tyrosine kinases, is shown to be phosphorylated at serine 25, a site very close to the major site of tyrosine phosphorylation by pp60v-src, tyrosine 23 (J. R. Glenney, Jr., and B. F. Tack, Proc. Natl. Acad. Sci. USA 82:7884-7888, 1985). We present evidence suggesting that prot...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gould KL,Woodgett JR,Isacke CM,Hunter T

    更新日期:1986-07-01 00:00:00

  • Site-specific acetylation by p300 or CREB binding protein regulates erythroid Krüppel-like factor transcriptional activity via its interaction with the SWI-SNF complex.

    abstract::Recruitment of modifiers and remodelers to specific DNA sites within chromatin plays a critical role in controlling gene expression. The study of globin gene regulation provides a convergence point within which to address these issues in the context of tissue-specific and developmentally regulated expression. In this ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Zhang W,Kadam S,Emerson BM,Bieker JJ

    更新日期:2001-04-01 00:00:00

  • The ht beta gene encodes a novel CACCC box-binding protein that regulates T-cell receptor gene expression.

    abstract::A gene encoding a novel CACCC box-binding protein that binds to the promoter region of the human T-cell receptor (TCR) V beta 8.1 gene and the mouse TCR alpha gene silencer has been cloned. This gene, termed ht beta, contains four zinc fingers of the class Cys2-X12-His2 that may be responsible for DNA binding and a hi...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wang Y,Kobori JA,Hood L

    更新日期:1993-09-01 00:00:00

  • An apparent pseudo-exon acts both as an alternative exon that leads to nonsense-mediated decay and as a zero-length exon.

    abstract::Pseudo-exons are intronic sequences that are flanked by apparent consensus splice sites but that are not observed in spliced mRNAs. Pseudo-exons are often difficult to activate by mutation and have typically been viewed as a conceptual challenge to our understanding of how the spliceosome discriminates between authent...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Grellscheid SN,Smith CW

    更新日期:2006-03-01 00:00:00

  • Phenotypic characterization of the murine Nkx2.6 homeobox gene by gene targeting.

    abstract::The NK-2 homeobox genes have been shown to play critical roles in the development of specific organs and tissues. Nkx2.6 is a member of the NK-2 homeobox gene family and is most closely related to the Drosophila tinman gene. Nkx2.6 is expressed in the caudal pharyngeal pouches, the caudal heart progenitors, the sinus ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Tanaka M,Yamasaki N,Izumo S

    更新日期:2000-04-01 00:00:00

  • Regulation of mouse CYP1A1 gene expression by dioxin: requirement of two cis-acting elements during induction.

    abstract::The mouse cytochrome P1450 (CYP1A1) gene is responsible for the metabolism of numerous carcinogens and toxic chemicals. Induction by the environmental contaminant tetrachlorodibenzo-p-dioxin (TCDD) requires a functional aromatic hydrocarbon (Ah) receptor. We examined the 5'-flanking region of the CYP1A1 gene in mouse ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Neuhold LA,Shirayoshi Y,Ozato K,Jones JE,Nebert DW

    更新日期:1989-06-01 00:00:00

  • Canonical and noncanonical g-protein signaling helps coordinate actin dynamics to promote macrophage phagocytosis of zymosan.

    abstract::Both chemotaxis and phagocytosis depend upon actin-driven cell protrusions and cell membrane remodeling. While chemoattractant receptors rely upon canonical G-protein signaling to activate downstream effectors, whether such signaling pathways affect phagocytosis is contentious. Here, we report that Gαi nucleotide exch...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Huang NN,Becker S,Boularan C,Kamenyeva O,Vural A,Hwang IY,Shi CS,Kehrl JH

    更新日期:2014-11-15 00:00:00

  • Retinoid X receptor:vitamin D3 receptor heterodimers promote stable preinitiation complex formation and direct 1,25-dihydroxyvitamin D3-dependent cell-free transcription.

    abstract::The numerous members of the steroid/nuclear hormone receptor superfamily act as direct transducers of circulating signals, such as steroids, thyroid hormone, and vitamin or lipid metabolites, and modulate the transcription of specific target genes, primarily as dimeric complexes. The receptors for 9-cis retinoic acid ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Lemon BD,Fondell JD,Freedman LP

    更新日期:1997-04-01 00:00:00

  • The tumor promoter 12-O-tetradecanoylphorbol-13-acetate and the ras oncogene modulate expression and phosphorylation of gap junction proteins.

    abstract::Gap junctional intercellular communication is inhibited in response to tumor promoters and oncogene transformation, suggesting that loss of this function is an important step in tumor formation. To elucidate the molecular mechanisms responsible for this inhibition, we examined the expression of gap junction proteins a...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Brissette JL,Kumar NM,Gilula NB,Dotto GP

    更新日期:1991-10-01 00:00:00

  • Identification of cis and trans components of a novel heat shock stress regulatory pathway in Saccharomyces cerevisiae.

    abstract::The stress-responsive DDR2 gene (previously called DDRA2) of Saccharomyces cerevisiae is transcribed at elevated levels following stress caused by heat shock or DNA damage. Previously, we identified a 51-bp promoter fragment, oligo31/32, which conferred heat shock inducibility on the heterologous CYC1-lacZ reporter ge...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kobayashi N,McEntee K

    更新日期:1993-01-01 00:00:00

  • Rat metallothionein-1 structural gene and three pseudogenes, one of which contains 5'-regulatory sequences.

    abstract::As shown by Southern blot analysis, the metallothionein-1 (MT-1) genes in rats comprise a multigene family. We present the sequence of the MT-1 structural gene and compare its features with other metallothionein genes. Three MT-1 pseudogenes which we sequenced apparently arose by reverse transcription of processed mRN...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Andersen RD,Birren BW,Taplitz SJ,Herschman HR

    更新日期:1986-01-01 00:00:00

  • The ARID family transcription factor bright is required for both hematopoietic stem cell and B lineage development.

    abstract::Bright/Arid3a has been characterized both as an activator of immunoglobulin heavy-chain transcription and as a proto-oncogene. Although Bright expression is highly B lineage stage restricted in adult mice, its expression in the earliest identifiable hematopoietic stem cell (HSC) population suggests that Bright might h...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Webb CF,Bryant J,Popowski M,Allred L,Kim D,Harriss J,Schmidt C,Miner CA,Rose K,Cheng HL,Griffin C,Tucker PW

    更新日期:2011-03-01 00:00:00

  • The human SPT20-containing SAGA complex plays a direct role in the regulation of endoplasmic reticulum stress-induced genes.

    abstract::One of the central questions in eukaryotic transcription is how activators can transmit their signal to stimulate gene expression in the context of chromatin. The multisubunit SAGA coactivator complex has both histone acetyltransferase and deubiquitination activities and remodels chromatin to allow transcription. Whet...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Nagy Z,Riss A,Romier C,le Guezennec X,Dongre AR,Orpinell M,Han J,Stunnenberg H,Tora L

    更新日期:2009-03-01 00:00:00

  • Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors.

    abstract::The vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactivati...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Tolón RM,Castillo AI,Jiménez-Lara AM,Aranda A

    更新日期:2000-12-01 00:00:00

  • Identification of histone mutants that are defective for transcription-coupled nucleosome occupancy.

    abstract::Our previous studies of Saccharomyces cerevisiae described a gene repression mechanism where the transcription of intergenic noncoding DNA (ncDNA) (SRG1) assembles nucleosomes across the promoter of the adjacent SER3 gene that interfere with the binding of transcription factors. To investigate the role of histones in ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hainer SJ,Martens JA

    更新日期:2011-09-01 00:00:00

  • The morphogenesis checkpoint in Saccharomyces cerevisiae: cell cycle control of Swe1p degradation by Hsl1p and Hsl7p.

    abstract::In Saccharomyces cerevisiae, the Wee1 family kinase Swe1p is normally stable during G(1) and S phases but is unstable during G(2) and M phases due to ubiquitination and subsequent degradation. However, perturbations of the actin cytoskeleton lead to a stabilization and accumulation of Swe1p. This response constitutes ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: McMillan JN,Longtine MS,Sia RA,Theesfeld CL,Bardes ES,Pringle JR,Lew DJ

    更新日期:1999-10-01 00:00:00