The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90

Tsuji, Noriko M.; Fukuda, Kana; Nagata, Yuhtaroh; Okada, Hirotaka; Haga, Asami; Hatakeyama, Shiori; Yoshida, Shizuo; Okamoto, Tomoya; Hosaka, Miki; Sekine, Kazuyoshi; Ohtaka, Kei; Yamamoto, Soh; Otaka, Michiro; Grave, Ewa; Itoh, Hideaki

doi:10.1016/j.fob.2014.09.003

Cited by 93 publications

(100 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5E). AhR forms a complex with the chaperone HSP90 in HeLa cells (33). Therefore, when we performed an immunoprecipitation assay to determine whether HSP90 formed a complex with AhR or c-Fos in RANKL-stimulated prefusion osteoclasts, we found that HSP90 coimmunoprecipitated with AhR or c-Fos (Fig.…”

Section: Effect Of Bap On Ahr Signaling and The Interaction Between Amentioning

confidence: 89%

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

Izawa

Arakaki

Mori

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)–mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow–derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR−/− mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos–dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR−/− mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.

show abstract

Section: Effect Of Bap On Ahr Signaling and The Interaction Between Amentioning

confidence: 89%

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

Izawa

Arakaki

Mori

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We speculate the pathway TCDD exerts its toxicity and other epigenetic effect could be account for the special effect in the higher group. TCDD exerts its toxic effects through AhR, which is translocated to nucleus in complex with the molecular chaperone Hsp90 (Tsuji et al, 2014). Hsp90 could be temporally induced as a protective mechanism against TCDD induced hepatotoxicity, and then be depressed with prolonged exposure (Kim et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

Chen

Liu

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Ancestral TCDD exposure could induce epigenetic transgenerational phenotypes, which may be mediated in part by imprinted gene inheritance. The aim of our study was to evaluate the transgenerational effects of ancestral TCDD exposure on the imprinted gene insulin-like growth factor-2 (Igf2) in rat somatic tissue. TCDD was administered daily by oral gavage to groups of F0 pregnant SD rats at dose levels of 0 (control), 200 or 800 ng/kg bw during gestation day 8-14. Animal transgenerational model of ancestral exposure to TCDD was carefully built, avoiding sibling inbreeding. Hepatic Igf2 expression of the TCDD male progeny was decreased concomitantly with hepatic damage and increased activities of serum hepatic enzymes both in the F1 and F3 generation. Imprinted Control Region (ICR) of Igf2 manifested a hypermethylated pattern, whereas methylation status in the Differentially Methylated Region 2 (DMR2) showed a hypomethylated manner in the F1 generation. These epigenetic alterations in these two regions maintained similar trends in the F3 generation. Meanwhile, the expressions of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) changed in a non-monotonic manner both in the F1 and F3 generation. This study provides evidence that ancestral TCDD exposure may promote epigenetic transgenerational alterations of imprinted gene Igf2 in adult somatic tissue.

show abstract

“…The molecular chaperone HSP90 regulates the physiological functions of more than 300 proteins including the steroid hormone receptors in the cells [1] [2]. We reported the activation mechanisms of AHR by HSP90 [9]. We also reported that AhR binds to the HSP90 N-domain [10].…”

Section: Discussionmentioning

confidence: 85%

“…The rabbit polyclonal antibodies against HSP90, XAP2, and p23 were previously described [3] [9] [10].…”

Section: Antibodiesmentioning

confidence: 99%

See 1 more Smart Citation

Cisplatin Inhibits AhR Activation

Sasaki-Kudoh¹,

Kudo²,

Kakizaki³

et al. 2018

AJMB

Self Cite

View full text Add to dashboard Cite

The AhR binds to contain ligands, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, 3-methylcholantrene, or β-naphthoflavone. The activation mechanism of AhRis not yet fully understood, but it is known that AhR associates with the molecular chaperone HSP90 in the cytoplasm. There are a few reports about the association or dissociation of AhR and HSP90, and which domain of HSP90 binds to AhR. We reported the association and activation mechanisms between HSP90 and AhR-PAS or AhR-bHLH. In the current study, we found that cisplatin inhibits the AhR activation. Although ATP and 17-DMAG have no effect on the dissociation of HSP90 from AhR, some contents of HSP90 were dissociated from AhR in the presence of cisplatin. We could detect the increase of CYP1A in the presence of 3-MC. On the contrary, the induction of CYP1A1 was inhibited in the presence of cisplatin. We couldn't detect AhR in the HeLa cell soluble fraction in the presence of 50 μM cisplatin. In the presence of MG-132, we could detect AhR. These results suggested that AhR was dissociated from the HSP90 chaperone complex and processed during the protein proteasome degradation system in the presence of cisplatin.

show abstract

The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90

Cited by 93 publications

References 24 publications

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

Cisplatin Inhibits AhR Activation

Contact Info

Product

Resources

About