Heat shock protein hsp90 regulates dioxin receptor function in vivo.

Whitelaw, Murray L.; McGuire, Jacqueline; Picard, Didier; Gustafsson, Jan‐Åke; Poellinger, Lorenz

doi:10.1073/pnas.92.10.4437

Cited by 110 publications

(81 citation statements)

References 32 publications

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“…Thus, Hsp90 may have a dual role: it ensures that receptors are kept inactive in the absence of hormone and helps them to respond specifically and efficiently to ligand. This view is also corroborated by pharmacological in vivo experiments with geldanamycin (Whitesell et al, 1994), a compound that interferes with certain Hsp90 functions such as the proper maturation of steroid receptor-Hsp90 complexes (Smith et al, 1995;Whitesell and Cook, 1996;Bamberger et al, 1997;Czar et al, 1997;Segnitz and Gehring, 1997).There is ample evidence for a role of Hsp90 in regulating the activity of several other signaling pathways, such as the xenobiotic response mediated by the dioxin receptor (see for example Pongratz et al, 1992;Carver et al, 1994;McGuire et al, 1994;Antonsson et al, 1995;Coumailleau et al, 1995;Whitelaw et al, 1995). Interaction of the dioxin receptor with Hsp90 is essential for ligand binding and for acquiring a DNAbinding conformation.…”

mentioning

confidence: 53%

“…There is ample evidence for a role of Hsp90 in regulating the activity of several other signaling pathways, such as the xenobiotic response mediated by the dioxin receptor (see for example Pongratz et al, 1992;Carver et al, 1994;McGuire et al, 1994;Antonsson et al, 1995;Coumailleau et al, 1995;Whitelaw et al, 1995). Interaction of the dioxin receptor with Hsp90 is essential for ligand binding and for acquiring a DNAbinding conformation.…”

Section: Introductionmentioning

confidence: 99%

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Hsp90 Is Required for Pheromone Signaling in Yeast

Louvion

Abbas-Terki

Picard

1998

MBoC

107

129

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The heat-shock protein 90 (Hsp90) is a cytosolic molecular chaperone that is highly abundant even at normal temperature. Specific functions for Hsp90 have been proposed based on the characterization of its interactions with certain transcription factors and kinases including Raf in vertebrates and flies. We therefore decided to address the role of Hsp90 for MAP kinase pathways in the budding yeast, an organism amenable to both genetic and biochemical analyses. We found that both basal and induced activities of the pheromone-signaling pathway depend on Hsp90. Signaling is defective in strains expressing low levels or point mutants of yeast Hsp90 (Hsp82), or human Hsp90␤ instead of the wild-type protein. Ste11, a yeast equivalent of Raf, forms complexes with wild-type Hsp90 and depends on Hsp90 function for accumulation. For budding yeast, Ste11 represents the first identified endogenous "substrate" of Hsp90. Moreover, Hsp90 functions in steroid receptor and pheromone signaling can be genetically separated as the Hsp82 point mutant T525I and the human Hsp90␤ are specifically defective for the former and the latter, respectively. These findings further corroborate the view that molecular chaperones must also be considered as transient or stable components of signal transduction pathways. INTRODUCTIONThe 90-kDa heat-shock protein (Hsp90) 1 (for reviews, see Jakob and Buchner, 1994;Csermely et al., 1998) is an ubiquitous and abundantly expressed cytosolic protein even at normal temperature. It is highly conserved from bacteria to mammals. Two genes encode closely related isoforms in mammals as well as in the budding yeast Saccharomyces cerevisiae. Deletion experiments in yeast have shown that the expression of at least one of the two Hsp90 isoforms, either Hsp82 or Hsc82, is essential for viability (Borkovich et al., 1989). Similarly, many mutant alleles of the Drosophila HSP90 homolog, HSP83, are embryonic lethals over a deficiency of the locus (van der Straten et al., 1997), whereas the Escherichia coli homolog of Hsp90, HtpG, appears to be dispensable (Bardwell and Craig, 1988). Hsp90 can act as a molecular chaperone in vitro to promote refolding of denatured proteins (Wiech et al., 1992;Yonehara et al., 1996; see also Shaknovich et al., 1992;Shue and Kohtz, 1994), to hold denatured proteins in a folding-competent state for other chaperones (Freeman and Morimoto, 1996;Yonehara et al., 1996) and to prevent protein unfolding and aggregation (Miyata and Yahara, 1992;Jakob et al., 1995aJakob et al., , 1995bYonehara et al., 1996).The interaction of Hsp90 with steroid receptors, which can be thought of as a signal transduction complex, has been the most extensively investigated. A variety of in vitro and in vivo studies have revealed that steroid receptors are complexed with Hsp90 and several other proteins in the absence of hormone (for review, see Pratt and Toft, 1997). Upon ligand binding, the hormone binding domain (HBD) undergoes a conformational change that results in the release of Hsp90 and the concomitant acti...

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mentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Hsp90 Is Required for Pheromone Signaling in Yeast

Louvion

Abbas-Terki

Picard

1998

MBoC

107

129

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“…To construct the glucocorticoid receptor/ mouse dioxin receptor deletion constructs for expression in mammalian cells, a ClaI/XbaI fragment was isolated from pDR⌬LBD/Gem and pDR⌬PASB/Gem and subcloned into ClaI/XbaI-digested pGRDBD/ CMV4 to give pGRDBD/DR⌬LBD/CMV4 and pGRDBD/DR⌬PASB/ CMV4, respectively. The yeast expression vectors pGRDBD/2HG and pGRDBDmDR/2HG (previously referred to as pGRDBDmDR83-805/ 2HG) have been described (22). To construct the glucocorticoid receptor/ mouse dioxin receptor deletion constructs for expression in yeast, an NcoI fragment was isolated from pDR⌬LBD/Gem and pDR⌬PASB/Gem and subcloned into NcoI-digested pGRDBDmDR/2HG to give pGRDBD/ DR⌬LBD/2HG and pGRDBD/DR⌬PASB/2HG, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Transformation of GRS4 with expression plasmids for the indicated glucocorticoid receptor/dioxin receptor fusion proteins together with the reporter plasmid pUC⌬SS26X was carried out using a modification of the lithium acetate method (30). Quantitation of ␤-galactosidase reporter gene activity in GRS4 transformants was carried out as described previously (22).…”

Section: Methodsmentioning

confidence: 99%

“…It has not yet been determined how the ligand-binding domain modulates this repressive activity. However, since hsp90 binding has been shown to colocalize within this region, it has been suggested that hsp90 itself may function as the agent of repression either by steric interference or by misfolding of adjacent structures (19,22). We were interested to determine whether deletion of the minimal region of the dioxin receptor harboring the ligand-and hsp90-binding activities of the receptor would result in a protein that was uncoupled from regulation by dioxin.…”

Section: A Dioxin Receptor Deletion Mutant Lacking the Minimal Lbd Ismentioning

confidence: 99%

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Definition of a Dioxin Receptor Mutant That Is a Constitutive Activator of Transcription

McGuire

Okamoto

Whitelaw

et al. 2001

Journal of Biological Chemistry

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The intracellular dioxin (aryl hydrocarbon) receptor is a ligand-activated transcription factor that mediates the adaptive and toxic responses to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and structurally related congeners. Whereas the ligand-free receptor is characterized by its association with the molecular chaperone hsp90, exposure to ligand initiates a multistep activation process involving nuclear translocation, dissociation from the hsp90 complex, and dimerization with its partner protein Arnt. In this study, we have characterized a dioxin receptor deletion mutant lacking the minimal ligand-binding domain of the receptor. This mutant did not bind ligand and localized constitutively to the nucleus. However, this protein was functionally inert since it failed to dimerize with Arnt and to bind DNA. In contrast, a dioxin receptor deletion mutant lacking the minimal PAS B motif but maintaining the N-terminal half of the ligand-binding domain showed constitutive dimerization with Arnt, bound DNA, and activated transcription in a ligand-independent manner. Interestingly, this mutant showed a more potent functional activity than the dioxin-activated wild-type receptor in several different cell lines. In conclusion, the constitutively active dioxin receptor may provide an important mechanistic tool to investigate receptor-mediated regulatory pathways in closer detail.The intracellular dioxin receptor also known as the aryl hydrocarbon receptor, is a ligand-dependent transcription factor that mediates the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1 commonly known as dioxin (1). Although disruption of the dioxin receptor gene in mice has not yielded conclusive results, it remains a possible scenario that physiological mechanisms may exist for activation of receptor function, e.g. during critical stages of vertebrate development (2-5). However, an endogenous ligand for the receptor has not yet been identified, suggesting that alternative pathways for receptor activation may exist.In the absence of ligand, the dioxin receptor is generally found in the cytoplasm associated in high molecular weight complexes comprising a dimer of the molecular chaperone hsp90, an immunophilin homolog known as XAP2 (hepatitis B virus X-associated protein-2)/AIP (aryl hydrocarbon receptorinteracting protein)/ARA9 (aryl hydrocarbon receptor-associated protein-9), and the co-chaperone p23 (6 -11). In the presence of dioxin, the receptor is converted to a functional DNAbinding species in a multistep process involving nuclear translocation, dissociation from the hsp90 complex, and dimerization with its partner protein Arnt (Ah receptor nuclear translocator). Formation of the dioxin receptor/Arnt heterodimer is a prerequisite for DNA binding and promotes transcription of target genes including those encoding xenobioticmetabolizing enzymes such as CYP1A1 (1). Both the dioxin receptor and Arnt are members of a distinct subclass of the basic helix-loop-helix (bHLH) family of transcriptional regul...

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Overview of AHR Functional Domains and the Classical AHR Signaling Pathway: Induction of Drug Metabolizing Enzymes

2011

The AH Receptor in Biology and Toxicology

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Heat shock protein hsp90 regulates dioxin receptor function in vivo.

Abstract: The dioxin (aryl hydrocarbon) receptor is a ligand-dependent basic helix-loop-helix (bHLH)

Cited by 110 publications

References 32 publications

Hsp90 Is Required for Pheromone Signaling in Yeast

Hsp90 Is Required for Pheromone Signaling in Yeast

Definition of a Dioxin Receptor Mutant That Is a Constitutive Activator of Transcription

Overview of AHR Functional Domains and the Classical AHR Signaling Pathway: Induction of Drug Metabolizing Enzymes

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