A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor–Arnt heterodimer

Sogawa, Kazuhiro; Numayama-Tsuruta, Keiko; Takahashi, Tomohiro; Matsushita, Natsuki; Miura, Chisa; Nikawa, Jùn‐ichi; Gotoh, Osamu; Kikuchi, Yasuo; Fujii‐Kuriyama, Yoshiaki

doi:10.1016/j.bbrc.2004.04.090

Cited by 94 publications

(67 citation statements)

References 35 publications

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“…In fact, it is known that in some cases, AhR can bind to DNA without a typical DRE motif. For instance, a DRE-like sequence (GCGGG) in the Pon1 promoter was involved in the recognition of AhR (Gouedard et al, 2004), and the AhR bound to the Cyp1A2 enhancer without a DRE only in the presence of unknown additional cellular factors coordinating specific AhR-DNA interaction (Sogawa et al, 2004). These findings suggest that the AhR was able to bind the 38 DRE-negative frag- ments because of degeneracy of the DRE sequence or possible coordinators.…”

Section: Discussionmentioning

confidence: 95%

“…To our knowledge, only a limited number of functional AhR-binding sites have been identified, mostly within the promoter regions of AhR-regulated genes (Sun et al, 2004;Tijet et al, 2006), including Cyp1A1 (Cytochrome P450, 1A1) (Denison et al, 1988;Lusska et al, 1993), Cyp1A2 (Cytochrome P450, 1A2) (Quattrochi et al, 1998;Sogawa et al, 2004), Cyp1B1 (Cytochrome P450, 1B1) (Eltom et al, 1999), Nqo1 (NAD(P)H: quinone oxidoreductase 1) (Favreau and Pickett, 1991), Ugt1A1 (UDPglucuronosyltransferase 1A1) (Emi et al, 1996), Gsta1 (Glutathione S-transferase Ya) (Pimental et al, 1993), Aldh3A1 (Aldehyde dehydrogenase 3A1) (Boesch et al, 1999), Nrf2 (NF-E2 p45-related factor) (Miao et al, 2005), Pon1 (Paraoxonase 1) (Gouedard et al, 2004), Cyp19A1 (P450 aromatase) (Baba et al, 2005), c-myc (Yang et al, 2005), Cyp2S1 (Cytochrome P450, 2S1) (Rivera et al, 2007), and Cyp2A5 (Cytochrome P450, 2A5) (Arpiainen et al, 2005); Cyp1A1 and Cyp1B1 being studied most extensively as model AhR-induced genes. Previous gene expression profiling by the DNA microarray technique in mouse hepatoma Hepa-1c1c7 cells stimulated with TCDD revealed that at least 285 genes exhibited obvious changes in their expression (Dere et al, 2006), but experimental genome-wide research for direct AhR-target genes has not been carried out so far.…”

Section: Introductionmentioning

confidence: 99%

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High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

et al. 2008

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

et al. 2008

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“…These proteins play signature roles in the detection of and adaptation to cellular changes, including responses to environmental contaminants, oxygen deprivation, biological rhythms, angiogenesis, and neuron development. [1][2][3] ARNTs differ from other PAS proteins in that they can dimerize with themselves as well as with other PAS proteins such as AHR, HIF-1a, and endothelial PAS domain protein 1 (EPAS-1). [4][5][6] For example, the AHR=ARNT heterodimer plays a pivotal role in mediating cellular responses to environmental contaminants such as polychlorinated dibenzo-pdioxins, dibenzofurans, and biphenyls and polyaromatic hydrocarbons through a well-characterized AHR=ARNT signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Potential Roles of Arnt2 in Zebrafish Larval Development

Hill

Heiden²,

Heideman³

et al. 2009

Zebrafish

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The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2 À=À ) mutant to identify functions of Arnt2 during development. Arnt2 À=À mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2 À=À larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2 À=À larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2 À=À mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2 À=À phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2 À=À larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

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“…Based on previous bioinformatic analyses (Sawaya and Riddick, 2008), we have focused on the proximal 10.1-kb region of the 5Ј-flank. This region is particularly enriched for DRE-like motifs (also known as AHRE-I elements) and also contains one perfect match to the AHRE-II consensus sequence, a novel site first identified in the CYP1A2 gene that binds an unknown factor that recruits the AHR ⅐ ARNT complex as a coactivator (Boutros et al, 2004;Sogawa et al, 2004). This region also contains putative sites for TFs involved in GH regulation of this gene (STAT5 and HNF-3) (Park and Waxman, 2001;Timsit and Riddick, 2002) and NF-B response elements that can mediate suppression of this gene by inflammatory cytokines (Iber et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P450 2C11 5′-Flanking Region and Promoter Mediate in Vivo Suppression by 3-Methylcholanthrene

Sawaya

Riddick²

2008

Drug Metab Dispos

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ABSTRACT:Aromatic hydrocarbons such as 3-methylcholanthrene (MC) elicit toxic and adaptive responses through the aryl hydrocarbon receptor (AHR). Aromatic hydrocarbons act via an unknown mechanism to suppress the transcription of CYP2C11, a growth hormoneregulated gene encoding the male-specific rat hepatic cytochrome P450 2C11. We hypothesize that suppression of CYP2C11 by aromatic hydrocarbons is mediated by the gene's promoter and 5-flank. Using hydrodynamics-based injections to deliver plasmid DNA to the liver of live rats, we studied the MC responsiveness of luciferase constructs containing 10.1, 5.6, and 2.4 kilobases (kb) of the CYP2C11 5-flank. MC suppressed CYP2C11-luciferase activity of the 10.1-and 5.6-kb constructs to less than 50% of vehicle levels by 24 and 72 h. Luciferase activity of the 2.4-kb CYP2C11 construct was decreased to 63% of vehicle levels 24 h after MC treatment, but no suppression was detected by 72 h. Negative regulatory element(s) responsible for CYP2C11 reporter suppression by MC exist in the proximal 2.4 kb of the 5-flank; however, additional cisacting elements located between ؊5.6 and ؊2.4 kb mediate persistent reporter suppression. As a positive control for AHR activation, MC dramatically induced the luciferase activity of a Cyp1a1-driven luciferase plasmid under AHR control. Modulation of reporter gene activity by MC was accompanied by induction of endogenous CYP1A1 and suppression of endogenous CYP2C11 mRNA/protein. This is the first demonstration of aromatic hydrocarbon-mediated suppression of a CYP2C11-luciferase construct, and this finding suggests that the 5-flanking region and promoter mediate downregulation of this gene in the intact rat.

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A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor–Arnt heterodimer

Cited by 94 publications

References 35 publications

High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Potential Roles of Arnt2 in Zebrafish Larval Development

Cytochrome P450 2C11 5′-Flanking Region and Promoter Mediate in Vivo Suppression by 3-Methylcholanthrene

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