Could HIF1B (DIOXIN RECEPTOR, ARYL HYDROCARBON RECEPTOR NUCLEAR translocator, ARNT, hypoxia-inducible factor 1 subunit BETA, BETA-HIF1), which constitutes together with HIF1-alpha, the "HIF1 heterodimer", be one of the links between mTOR and the estrogen receptor?
Furthermore, the gene "aryl hydrocarbon receptor nuclear translocator-ARNT" has 99% homology with the cathepsin K gene (CTSK), whose protein is strongly expressed in all the visceral lesions of tuberous sclerosis.
Biochemical and Biophysical Research Communications
Available online 2 June 2014
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Aryl hydrocarbon receptor catabolic activity in bone metabolism is osteoclast dependent in vivo
Tai-yong Yua, b, Takeshi Kondoc, Takahiro Matsumotoc, Yoshiaki Fujii-Kuriyamad, Yuuki Imaia, b
DOI: 10.1016/j.bbrc.2014.05.114
Abstract
Bone mass is regulated by various molecules including endogenous factors as well as exogenous factors, such as nutrients and pollutants. Aryl hydrocarbon receptor (AhR) is known as a dioxin receptor and is responsible for various pathological and physiological processes. However, the role of AhR in bone homeostasis remains elusive because the cell type specific direct function of AhR has never been exploredin vivo. Here, we show the cell type specific function of AhR in vivo in bone homeostasis. Systemic AhR knockout (AhRKO) mice exhibit increased bone mass with decreased resorption and decreased formation. Meanwhile, osteoclast specific AhRKO (AhRΔOc/ΔOc) mice have increased bone mass with reduced bone resorption, although the mice lacking AhR in osteoblasts have a normal bone phenotype. Even under pathological conditions, AhRΔOc/ΔOc mice are resistant to sex hormone deficiency-induced bone loss resulting from increased bone resorption. Furthermore, 3-methylcholanthrene, an AhR agonist, induces low bone mass with increased bone resorption in control mice, but not in AhRΔOc/ΔOc mice. Taken together, cell type specific in vivo evidence for AhR functions indicates that osteoclastic AhR plays a significant role in maintenance of bone homeostasis, suggesting that inhibition of AhR in osteoclasts can be beneficial in the treatment of osteoporosis.
The attached photo is from: ORIGINAL RESEARCH ARTICLE Front. Pharmacol., 02 November 2010 | doi: 10.3389/fphar.2010.00129
Pathway-targeted pharmacogenomics of CYP1A2 in human liver
Kathrin Klein1 *, Stefan winter1, Miia Turpeinen1, Matthias Schwab1, 2 and Ulrich M. Zanger1
1 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tuebingen, Stuttgart, Germany
2 Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tuebingen, Tuebingen, Germany
Arnt-like protein 1 (BMAL1)
Article Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormali...
Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy
Abstract
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder.
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