Genetic and molecular analysis of the Ah receptor and of Cyp1a1 gene expression

Hankinson, Oliver; Brooks, Barbara A.; Weir-Brown, K.I.; Hoffman, Emily C.; Johnson, Barton S.; Nanthur, J; Reyes, Herminio; Watson, Andrea

doi:10.1016/0300-9084(91)90075-c

Cited by 53 publications

(29 citation statements)

References 29 publications

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“…Nuclear and cytoplasmic fractions were purified from mouse Hepa-1c1c7 (Hankinson et al 1991) and human BxPC3 cells (Yasutome et al 2005), from which total RNA (Schwanekamp et al 2006) and proteins (Yasutome et al 2005) were isolated from the same fractions using TRI reagent (Molecular Research Center). Two approaches were taken to demonstrate that the first criterion was satisfied, in which clean nuclear and cytoplasmic fractions were isolated (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Two diverse cell lines and experimental conditions were selected in order to more broadly test our hypothesis. The first set of experiments was a comparison of vehicle-treated and TCDDtreated mouse Hepa-1c1c7 hepatocyte cells (Hankinson et al 1991), and the second experimental set compared the relative RNA levels of sham vector (SMAD4 À/À ) and SMAD4-positive (Yasutome et al 2005) human BxPC3 pancreatic cancer cell lines (Tan et al 1986). The microarray results for selected genes were confirmed by quantitative real-time polymerase chain reaction assays using SYBR green and designed primers (Supplemental Tables S1, S2; Guo et al 2004).…”

Section: Resultsmentioning

confidence: 99%

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Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs

Trask¹,

Cowper-Sal·lari²,

Sartor³

et al. 2009

RNA

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With no known exceptions, every published microarray study to determine differential mRNA levels in eukaryotes used RNA extracted from whole cells. It is assumed that the use of whole cell RNA in microarray gene expression analysis provides a legitimate profile of steady-state mRNA. Standard labeling methods and the prevailing dogma that mRNA resides almost exclusively in the cytoplasm has led to the long-standing belief that the nuclear RNA contribution is negligible. We report that unadulterated cytoplasmic RNA uncovers differentially expressed mRNAs that otherwise would not have been detected when using whole cell RNA and that the inclusion of nuclear RNA has a large impact on whole cell gene expression microarray results by distorting the mRNA profile to the extent that a substantial number of false positives are generated. We conclude that to produce a valid profile of the steady-state mRNA population, the nuclear component must be excluded, and to arrive at a more realistic view of a cell's gene expression profile, the nuclear and cytoplasmic RNA fractions should be analyzed separately.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs

Trask¹,

Cowper-Sal·lari²,

Sartor³

et al. 2009

RNA

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“…Historically, the evolutionarily conserved AHR was studied for its ability, upon activation by environmental ligands, to regulate genes encoding a battery of cytochrome P450 enzymes that metabolize at least some of those ligands into metabolic intermediates, some of which are toxic (Hankinson et al, 1991;Nebert et al, 1991). Similarly, studies published over the last 20-30 years demonstrate the role of the AHR in the initiation of environmental chemical-induced cancers, to a large extent through P450-dependent generation of mutagenic intermediates.…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

et al. 2014

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The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy) acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)-and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC 50 3.3 Â 10 27 M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy.

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“…The basic-helix-loop-helix (bHLH)-PER-ARNT-SIM (PAS) superfamily plays crucial roles in adaptive responses to low atmospheric and cellular oxygen levels, exposure to certain environmental pollutants, and diurnal oscillations in light and temperature [1][2][3]. MOP3, also known as aryl hydrocarbon receptor nuclear translocator 3 (ARNT3) or brain and muscle Arnt-like protein-1 (BMAL1), is a member of PAS superfamily, and a key transcription factor in the transcriptional/ translational feedback loop of mammalian circadian genes [4].…”

Section: Introductionmentioning

confidence: 99%

The mortality of MOP3 deficient mice with a systemic functional failure

Sun¹,

Yang

Niu

et al. 2006

J Biomed Sci

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SummaryMOP3 (also known as BMAL1), a master regulator of circadian rhythm, plays important roles in the regulation of cell differentiation and general physical functions. In the present studies, MOP3 deficient mice had significantly reduced body weight and showed remarkable mortality around six months of age. The levels of AST, ALT, BUN, or UREA in the blood of about four month-old MOP3 )/) mice were significantly higher than MOP3 +/) or MOP3 +/+ littermates. However, no apparent pathological changes in the livers, hearts, lungs or kidneys of about four month-old MOP3 )/) mice were observed. In addition, altered levels of white blood cells, lympgocytes, and platelets in peripheral blood of MOP3 )/) mice were detected. The results presented herein with MOP3-deficient mice offered the basic principle for the essential roles of MOP3 in keeping normal survival abilities in mice. This study may have significant clinical impacts on the consideration about the abnormality of circadian rhythms and sleeping disorders caused physical and metabolism dysfunctions as well as the mortality.Abbreviations: ALT -alanine aminotransferase; ARNT -aryl hydrocarbon receptor nuclear translocator; AST -asparate aminotransferase; bHLH -basic-helix-loop-helix domain; BMAL1 -brain and muscle Arnt-like protein-1; CLOCK -product of the clock locus in mice; HIF -hypoxia-inducible factor; PAS -PER-ARNT-SIM homology domain; SGPT -serum glutamic pyruvic transaminase; SGOT -serum glutamic oxalocetic transaminase

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Genetic and molecular analysis of the Ah receptor and of Cyp1a1 gene expression

Cited by 53 publications

References 29 publications

Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs

Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs

In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

The mortality of MOP3 deficient mice with a systemic functional failure

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