HonCode

Go Back   HER2 Support Group Forums > Articles of Interest
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 01-14-2010, 11:24 PM   #1
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Aryl-Hydrocarbon Receptor (AhR)

Mol Endocrinol. 2009 Dec 23. [Epub ahead of print]
Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation.

Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS.
The Hamner Institutes For Health Sciences (J.M.H., M.A.B., W.F.G., R.S.T.), Genomic Biology and Bioinformatics, Research Triangle Park, North Carolina 27709; and Duke University Medical Center (D.K., D.P.M.), Department of Pharmacology and Cancer Biology, Durham, North Carolina 27710.
The current statistics associated with breast cancer continue to show a relatively high recurrence rate together with a poor survival for aggressive metastatic disease. These findings reflect, in part, the pharmaceutical intractability of processes involved in the metastatic process and highlight the need to identify additional drug targets for the treatment of late-stage disease. In the current study, we report that ligand activation of the aryl-hydrocarbon receptor (AhR) inhibits multiple aspects of the metastatic process in a panel of breast cancer cell lines that represent the major breast cancer subtypes. Specifically, it was observed that treatment with exogenous AhR agonists significantly inhibited cell invasiveness and motility in the Boyden chamber assay and inhibited colony formation in soft agar regardless of estrogen receptor (ER), progesterone receptor, or human epidermal growth factor receptor 2 status. Knockdown of the AhR using small interfering RNA duplexes demonstrated that the inhibition of invasiveness was receptor dependent and that endogenous receptor activity was protective in each cell type examined. The inhibition of invasiveness and anchorage-independent growth correlated with the ability of exogenous AhR agonists to promote differentiation. Finally, exogenous AhR agonists were able to promote differentiation in a putative mammary cancer stem cell line. Cumulatively, these results suggest that the AhR plays an important role in mammary epithelial differentiation and, as such, represent a promising therapeutic target for a range of phenotypically distinct human breast cancers.

PMID: 20032195 [PubMed - as supplied by publisher]






Oncogene. 2005 Nov 24;24(53):7869-81.
The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells.

Yang X, Liu D, Murray TJ, Mitchell GC, Hesterman EV, Karchner SI, Merson RR, Hahn ME, Sherr DH.
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
The aryl hydrocarbon receptor (AhR) is an environmental carcinogen-activated transcription factor associated with tumorigenesis. High levels of apparently active AhR characterize a variety of tumors, even in the absence of environmental ligands. Despite this association between transformation and AhR upregulation, little is known of the transcriptional consequences of constitutive AhR activation. Here, the effects of constitutively active and environmental ligand-induced AhR on c-myc, an oncogene whose promoter contains six AhR-binding sites (AhREs (aryl hydrocarbon response elements)), were investigated. A reporter containing the human c-myc promoter, with its six AhREs and two NF-kappaB-binding sites, was constructed. This vector, and variants with deletions in the NF-kappaB and/or AhR-binding sites, was transfected into a human breast cancer cell line, Hs578T, which expresses high levels of apparently active, nuclear AhR. Results indicate that: (1) the AhR constitutively binds the c-myc promoter; (2) there is a low but significant baseline level of c-myc promoter activity, which is not regulated by NF-kappaB and is not affected by an environmental AhR ligand; (3) deletion of any one of the AhREs has no effect on constitutive reporter activity, while deletion of all six increases reporter activity approximately fivefold; (4) a similar increase in reporter activity occurs when constitutively active AhR is suppressed by transfection with an AhR repressor plasmid (AhRR); (5) AhRR transfection significantly increases background levels of endogenous c-myc mRNA and c-Myc protein. These results suggest that the AhR influences the expression of c-Myc, a protein critical to malignant transformation.

PMID: 16091746 [PubMed - indexed for MEDLINE]





Mol Cancer Res. 2009 Jun;7(6):977-86. Epub 2009 May 26.
Estrogen receptor subtype- and promoter-specific modulation of aryl hydrocarbon receptor-dependent transcription.

Wihlén B, Ahmed S, Inzunza J, Matthews J.
Department of Biosciences and Nutrition at Novum, Karolinska Institutet, Huddinge, Sweden.
In this study, we examined the role of estrogen receptors (ER) in aryl hydrocarbon receptor (AHR)-dependent transactivation. Chromatin immunoprecipitation assays showed that AHR agonists differentially induced recruitment of ERalpha to the AHR target genes CYP1A1 and CYP1B1. Cotreatment with 17beta-estradiol significantly increased beta-naphthoflavone (BNF)- and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced recruitment of ERalpha to CYP1A1, whereas 3,3'-diindolylmethane induced promoter occupancy of ERalpha at CYP1A1 that was unaffected by cotreatment with 17beta-estradiol. Cyclical recruitment of AHR and ERalpha to CYP1A1 was only observed in cells treated with BNF. Stable and subtype-specific knockdown of ERalpha or ERbeta using shRNA showed that suppression of ERalpha significantly reduced, whereas knockdown of ERbeta significantly enhanced, AHR agonist-induced Cyp1a1 expression in HC11 mouse mammary epithelial cells. AHR agonist-induced Cyp1b1 expression was reduced by ERbeta knockdown but unaffected by ERalpha knockdown. The siRNA-mediated knockdown of ERalpha in MCF-7 human breast cancer cells did not affect 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent regulation of CYP1A1 and CYP1B1 mRNA expression. In agreement with our in vitro findings in the HC11 cells, ERalpha knockout mice exhibit reduced BNF-dependent induction of Cyp1a1 mRNA. These results establish ligand- and promoter-specific influences on the cyclical recruitment patterns for AHR and show ER species-, subtype-, and promoter-specific modulation of AHR-dependent transcription.

PMID: 19470599 [PubMed - indexed for MEDLINE]






J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):295-306.
Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells.

Safe S, Wormke M, Samudio I.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA. ssafe@cvm.tamu.edu
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that forms a functional heterodimeric complex with the AhR nuclear translocator (Arnt) protein. The environmental toxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is a high affinity ligand for the AhR and has been extensively used to investigate AhR-mediated biochemical and toxic responses. TCDD modulates several endocrine pathways including inhibition of 17beta-estradiol-induced responses in the immature and ovariectomized rodent uterus and mammary gland and in human breast cancer cell lines. TCDD inhibits formation and growth of mammary tumors in carcinogen-induced rodent models and relatively nontoxic selective AhR modulators (SAhRMs) are being developed for treatment of breast cancer. The mechanisms of inhibitory AhR-estrogen receptor (ER) crosstalk have been investigated in MCF-7 breast cancer cells by analysis of promoter regions of genes induced by E2 and inhibited by TCDD. AhR-mediated inhibition of E2-induced cathepsin D, pS2, c-fos, and heat shock protein 27 gene expression involves direct interaction of the AhR complex with inhibitory pentanucleotide (GCGTG) dioxin responsive elements (iDREs) resulting in disruption of interactions between proteins binding DNA elements required for ER action and the basal transcription machinery. Mechanisms of inhibitory AhR-ER crosstalk indicate that functional iDREs are required for inhibition of some genes; however, results indicate that other interaction pathways are important including AhR-mediated proteasome-dependent degradation of the ER.

PMID: 14973392 [PubMed - indexed for MEDLINE]




Mol Cell Biol. 2005 Jul;25(13):5317-28.
Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters.

Matthews J, Wihlén B, Thomsen J, Gustafsson JA.
Department of Biosciences at Novum, Karolinska Institutet, Novum 14157, Sweden. jason.matthews@biosci.ki.se
Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor alpha (ERalpha) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by co-treatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ERalpha to the estrogen-responsive pS2 promoter, and after 120 min of co-treatment with estradiol, ERalpha is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ERalpha in TCDD-dependent CYP1A1 expression. Our data suggest that ERalpha acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ERalpha by AhR represents a novel mechanism AhR-ERalpha cross talk.

PMID: 15964790 [PubMed - indexed for MEDLINE]



Phytochemistry. 2008 Dec;69(18):3117-30. Epub 2007 Sep 14.
Influence of food polyphenols on aryl hydrocarbon receptor-signaling pathway estimated by in vitro bioassay.

Amakura Y, Tsutsumi T, Sasaki K, Nakamura M, Yoshida T, Maitani T.
College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan. amakura@cc.matsuyama-u.ac.jp
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxic and biological actions of many aromatic environmental pollutants such as dioxins. We investigated AhR activation by some vegetable constituents, including flavonoids, tannins, and related polyphenols, using an AhR-based in vitro bioassay for dioxins. Among the compounds tested, marked AhR activation was exhibited by isoflavones such as daidzein, resveratrol (a stilbene) structure, some flavanones such as naringenin, and flavones such as baicalein. On the other hand, some flavones such as apigenin, flavonols such as quercetin, and anthraquinones such as emodin, showed notable inhibitory effects on the in vitro activation of AhR induced by the dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)]. In addition, AhR-mediated interactions between AhR and some plant extracts, including those from vegetables, fruits, herbs, and teas, were tested by using the AhR-based bioassay. Of the samples tested, some leafy green vegetables, citrus fruits, and herbs that contain food polyphenolics showed AhR-based interactions at high concentrations. On the basis of these finding, we discuss the implications of polyphenols on the AhR-signaling pathway.

PMID: 17869316 [PubMed - indexed for MEDLINE]








Br J Cancer. 1999 Mar;79(9-10):1340-6.
The flavonoid galangin is an inhibitor of CYP1A1 activity and an agonist/antagonist of the aryl hydrocarbon receptor.

FULL TEXT

Ciolino HP, Yeh GC.
Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, NIH, MD 21702-1201, USA.
The effect of the dietary flavonoid galangin on the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA), the activity of cytochrome P450 1A1 (CYP1A1), and the expression of CYP1A1 in MCF-7 human breast carcinoma cells was investigated. Galangin inhibited the catabolic breakdown of DMBA, as measured by thin-layer chromatography, in a dose-dependent manner. Galangin also inhibited the formation of DMBA-DNA adducts, and prevented DMBA-induced inhibition of cell growth. Galangin caused a potent, dose-dependent inhibition of CYP1A1 activity, as measured by ethoxyresorufin-O-deethylase activity, in intact cells and in microsomes isolated from DMBA-treated cells. Analysis of the inhibition kinetics by double-reciprocal plot demonstrated that galangin inhibited CYP1A1 activity in a noncompetitive manner. Galangin caused an increase in the level of CYP1A1 mRNA, indicating that it may be an agonist of the aryl hydrocarbon receptor, but it inhibited the induction of CYP1A1 mRNA by DMBA or by 2,3,5,7-tetrachlorodibenzo-p-dioxin (TCDD). Galangin also inhibited the DMBA- or TCDD-induced transcription of a reporter vector containing the CYP1A1 promoter. Thus, galangin is a potent inhibitor of DMBA metabolism and an agonist/antagonist of the AhR, and may prove to be an effective chemopreventive agent.

PMID: 10188874 [PubMed - indexed for MEDLINE]


or..maybe it works in another way??:



Breast Cancer Res. 2006;8(2):R17. Epub 2006 Mar 27.
Growth of a human mammary tumor cell line is blocked by galangin, a naturally occurring bioflavonoid, and is accompanied by down-regulation of cyclins D3, E, and A.

FULL TEXT

Murray TJ, Yang X, Sherr DH.
Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.
INTRODUCTION: This study was designed to determine if and how a non-toxic, naturally occurring bioflavonoid, galangin, affects proliferation of human mammary tumor cells. Our previous studies demonstrated that, in other cell types, galangin is a potent inhibitor of the aryl hydrocarbon receptor (AhR), an environmental carcinogen-responsive transcription factor implicated in mammary tumor initiation and growth control. Because some current breast cancer therapeutics are ineffective in estrogen receptor (ER) negative tumors and since the AhR may be involved in breast cancer proliferation, the effects of galangin on the proliferation of an ER-, AhRhigh line, Hs578T, were studied. METHODS: AhR expression and function in the presence or absence of galangin, a second AhR inhibitor, alpha-naphthoflavone (alpha-NF), an AhR agonist, indole-3-carbinol, and a transfected AhR repressor-encoding plasmid (FhAhRR) were studied in Hs578T cells by western blotting for nuclear (for instance, constitutively activated) AhR and by transfection of an AhR-driven reporter construct, pGudLuc. The effects of these agents on cell proliferation were studied by 3H-thymidine incorporation and by flow cytometry. The effects on cyclins implicated in mammary tumorigenesis were evaluated by western blotting. RESULTS: Hs578T cells were shown to express high levels of constitutively active AhR. Constitutive and environmental chemical-induced AhR activity was profoundly suppressed by galangin as was cell proliferation. However, the failure of alpha-NF or FhAhRR transfection to block proliferation indicated that galangin-mediated AhR inhibition was either insufficient or unrelated to its ability to significantly block cell proliferation at therapeutically relevant doses (IC50 = 11 microM). Galangin inhibited transition of cells from the G0/G1 to the S phases of cell growth, likely through the nearly total elimination of cyclin D3. Expression of cyclins A and E was also suppressed.

CONCLUSION: Galangin is a strong inhibitor of Hs578T cell proliferation that likely mediates this effect through a relatively unique mechanism, suppression of cyclin D3, and not through the AhR. The results suggest that this non-toxic bioflavonoid may be useful as a chemotherapeutic, particularly in combination with agents that target other components of the tumor cell cycle and in situations where estrogen receptor-specific therapeutics are ineffective.

PMID: 16569260 [PubMed - indexed for MEDLINE]



Galangin: http://www.raysahelian.com/galangin.html
Quote:
Galangin, a member of the flavonol class of flavonoid, is present in high concentrations in medicinal plants (e.g. Alpinia officinarum) and propolis, a natural beehive product. Results from in vitro and in vivo studies indicate that galangin with anti-oxidative and free radical scavenging activities is capable of modulating enzyme activities and suppressing the genotoxicity of chemicals.
Mol Pharmacol. 2000 Sep;58(3):515-25.
The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis.

Quadri SA, Qadri AN, Hahn ME, Mann KK, Sherr DH.
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancers induced by common environmental chemicals. Much of the biologic activity of one such class of pollutants, polycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon receptor/transcription factor (AhR). For example, the AhR regulates PAH immunotoxicity that manifests as pre-B cell apoptosis in models of B cell development. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them would suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell development in which pre-B cells are cultured with and are dependent on bone marrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoids screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C(2)-ceramide- or H(2)O(2)-induced pre-B cell apoptosis. Because galangin blocked AhR-dependent reporter gene expression, AhR complex-DNA binding, and AhR nuclear translocation, inhibition of a relatively early step in AhR signaling was implicated. This hypothesis was supported by the ability of galangin to bind the AhR and stabilize AhR-90-kDa heat shock protein complexes in the presence of AhR agonists. These studies demonstrate the utility of pre-B cell culture systems in identifying compounds capable of blocking PAH immunotoxicity, define at least one mechanism of galangin activity (i.e., repression of AhR activation), and motivate the use of this and similar dietary bioflavonoids as relatively nontoxic inhibitors of AhR agonist activity and as pharmacologic agents with which to dissect AhR signaling pathways.

PMID: 10953044 [PubMed - indexed for MEDLINE]



Quote:
Known ligands of the AhR are, for the most part, man-made chemicals; natural ligands have been postulated but, with the exception of indolo[2,3]-carbazole (Jellinck et al, 1993), remain unidentified. We have hypothesized elsewhere (Ciolino et al, 1998) that dietary polyphenolic compounds are natural ligands of the AhR and galangin appears to be such a compound. These experiments demonstrate that galangin inhibits carcinogen activation in MCF-7 cells at two levels: through direct inhibition of CYP1A1 enzyme activity and by inhibiting the increase in CYP1A1 transcription caused by AhR ligands. There is no study, to our knowledge, on the chemopreventive effect of galangin in
animal models of carcinogenesis. Based on our data, galangin may be a promising candidate for in vivo chemoprevention studies.
Biosci Biotechnol Biochem. 2009 Jul;73(7):1635-9. Epub 2009 Jul 7.
Inhibition of P-glycoprotein enhances the suppressive effect of kaempferol on transformation of the aryl hydrocarbon receptor.

Mukai R, Satsu H, Shimizu M, Ashida H.
Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan.
Dioxins enter the body mainly through the diet, bind to the aryl hydrocarbon receptor (AhR), and cause various toxicological effects. In this study, we found that oral administration of kaempferol or ginkgo biloba extract (EGb) containing 24% flavonol at 100 mg/kg body weight suppressed AhR transformation induced by 3-methylcholanthrene at 10 mg/kg body weight in the liver of mice. The suppressive effect of kaempferol was enhanced by verapamil, an inhibitor of P-glycoprotein (P-gp), in ex vivo experiments using a hepatic cytosolic fraction and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Enhancement of the suppressive effect by verapamil was also observed in mouse hepatoma Hepa-1c1c7 cells, accompanied by an increase in the uptake of kaempferol into the cells. In conclusion, inhibition of P-gp enhanced the suppressive effect of kaempferol on AhR transformation through an increase in the intracellular kaempferol concentration.

PMID: 19584540 [PubMed - indexed for MEDLINE]



Good or Bad?:

J Agric Food Chem. 2008 Nov 12;56(21):10399-405. Epub 2008 Oct 18.
Cacao polyphenol extract suppresses transformation of an aryl hydrocarbon receptor in C57BL/6 mice.

Mukai R, Fukuda I, Nishiumi S, Natsume M, Osakabe N, Yoshida K, Ashida H.
Department of Agrobioscienec, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan.
Dioxins enter the body through the diet and cause various toxicological effects through transformation of an aryl hydrocarbon receptor (AhR). Plant extracts and phytochemicals including flavonoids are reported to suppress this transformation. This paper investigates the suppression by a cacao polyphenol extract (CPE) of AhR transformation in vivo. The CPE was administered orally to C57BL/6 mice at 100 mg/kg of body weight, followed 1 h later by 3-methylcholanthrene (MC), an AhR agonist, injected intraperitoneally at 10 mg/kg of body weight. CPE suppressed the MC-induced transformation to the control level by inhibiting the formation of a heterodimer between AhR and an aryl hydrocarbon receptor nuclear translocator in the liver at 3 h postadministration. It also suppressed MC-induced cytochrome P4501A1 expression and NAD(P)H:quinone-oxidoreductase activity, whereas it increased glutathione S-transferase activity at 25 h. CPE constituents and their metabolites might contribute, at least in part, to the suppression of AhR transformation. The results indicate that the intake of CPE suppressed the toxicological effects of dioxins in the body.

PMID: 18928297 [PubMed - indexed for MEDLINE]




Different from the receptor but putting it here in case someone can figure this out

Mol Carcinog. 2010 Feb;49(2):157-65.
Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth.

Shi S, Yoon DY, Hodge-Bell K, Huerta-Yepez S, Hankinson O.
Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095-1732, USA.
c4 is a derivative of the mouse hepatoma cell line, Hepa-1, that harbors a mutation in the aryl hydrocarbon receptor nuclear translocator gene (Arnt, or hypoxia inducible factor 1beta [HIF-1beta]) leading to loss of activity. Clone 3 cells were generated by introducing a doxycycline-repressible Arnt expression vector into c4 cells. Clone 3 cells were injected subcutaneously into immunosuppressed mice, which were treated with doxycyline (a) throughout the growth of the subsequent tumor xenografts, or (b) from day 7 through to the end of the experiment (day 30), or not treated (c). Tumors in all groups grew exponentially between days 14 and 30, and at rates that were indistinguishable from each other. However, tumors in group a were smaller than those of the other two groups throughout the measurable growth period, while tumor volumes in groups b and c were not significantly different from each other. The degrees of vascularity and apoptosis did not correlate with the differences in degrees of growth between the different groups. Thus, Arnt is required during the early stages of growth of the tumors but less in later stages. Since Arnt does not detectably effect the growth kinetics of Hepa-1 cells either during hypoxia or normoxia, this requirement is unlikely to reflect a direct effect of Arnt on cell proliferation, and is therefore probably a consequence of altered interaction(s) between the tumor cells and the host. These studies suggest that Arnt (and HIF-1alpha/HIF-2alpha) inhibitors will be particularly effective against smaller tumors, including micrometastases.

PMID: 19824022 [PubMed - in process]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 03-13-2010, 01:47 PM   #2
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Aryl-Hydrocarbon Receptor (AhR)

Circadian issues

Biochem Pharmacol. 2009 Feb 15;77(4):560-5. Epub 2008 Oct 15.
Crosstalk between the AHR signaling pathway and circadian rhythm.

Shimba S, Watabe Y.
Department of Health Science, College of Pharmacy, Nihon University, Funabashi, Chiba, Japan. shimba.shigeki@nihon-u.ac.jp
In this chapter, we review the crosstalk between the AHR signaling pathway and molecular clock system in mammals. In mammals, circadian rhythm is observed in most physiological functions including behavior, metabolism, cell growth, and immune responses. Circadian rhythm is regulated by a transcriptional feedback loop, and the transcription factor called "Brain Muscle ARNT-like protein 1 (BMAL1)" is a master regulator of this system. Because of its structural similarity to ARNT, a partner of AHR, BMAL1 is also referred as ARNT3. This structural feature of BMAL1 suggests that the activation of the AHR signaling pathway may influence the regulation of circadian rhythm. Several studies have shown that the expression levels of AHR display diurnal variation in many tissues. This circadian variation of AHR means that the pharmacological effects of AHR agonists vary according to the time of administration. AHR agonist administration results in a disruption of circadian rhythm with regard to behavior, immune cell proliferation, etc. As such, understanding the crosstalk between the AHR signaling and circadian rhythm may provide a new insight into TCDD actions.

PMID: 18983986 [PubMed - indexed for MEDLINE]




Toxicol Sci. 2010 Jan 27. [Epub ahead of print]
Disruption of Clock/BMAL1 Transcriptional Activity is Responsible for Aryl Hydrocarbon Receptor-Mediated Regulation of Period1 Gene.

Xu CX, Krager SL, Liao DF, Tischkau SA.
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, 62974-9629; cxu@siumed.edu.
The aryl hydrocarbon receptor (AhR) is a PER-ARNT-SIM (PAS) domain transcription factor that shares structural similarity with circadian clock genes and readily interacts with components of the molecular clock. Activation of AhR by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) alters behavioral circadian rhythms and represses the Period 1 (Per1) gene in murine hematopoietic stem and progenitor cells. Per1 expression is driven by CLOCK/BMAL1-dependent activation of Eboxes in the Per1 promoter. We hypothesized that the effects of AhR activation on the circadian clock are mediated by disruption of CLOCK/BMAL1 function and subsequent Per1 gene suppression. Effects of AhR activation on rhythmic Per1 transcripts were examined in livers of mice after treatment with the AhR agonist, 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8,-TCDD); the molecular mechanisms of Per1 repression by AhR were determined in hepatoma cells using TCDD and beta-napthoflavone (beta-NF) as AhR activators. This study reports, for the first time, that AhR activation by TCDD alters the Per1 rhythm in the mouse liver, and that Per1 gene suppression depends upon the presence of AhR. Furthermore, AhR interaction with BMAL1 attenuates CLOCK/BMAL1 activity and decreases CLOCK binding at Ebox1 and Ebox3 in the Per1 promoter. Taken together, these data suggest that AhR activation represses Per1 through disrupting CLOCK/BMAL1 activity, producing dysregulation of rhythmic Per1 gene expression. These data define alteration of the Per1 rhythm as novel signaling events downstream of AhR activation. Down-regulation of Per1 could contribute to metabolic disease, cancer and other detrimental effects resulting from exposure to certain environmental pollutants.

PMID: 20106950 [PubMed - as supplied by publisher]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 09:42 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter