HER2 Support Group Forums - View Single Post - Aryl-Hydrocarbon Receptor (AhR)

Rich66 · 03-13-2010, 01:47 PM

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]

03-13-2010, 01:47 PM	#2
Rich66 Senior Member 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)