Identification of a Novel Cis-acting Negative Regulatory Element Affecting Expression of the CYP1A1 Gene in Rat Epidermal Cells

Walsh, Agnes A.; Tullis, Kathryn; Rice, Robert H.; Denison, Michael S.

doi:10.1074/jbc.271.37.22746

Cited by 27 publications

(14 citation statements)

References 58 publications

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“…This is associated with differentiation at high passage numbers concomitant with down-regulation of Cyp1A1 and Cyp1B1 (27). A sequence similar to half of this element is found in the mouse Cyp1B1 region immediately downstream of the enhancer element in a position equivalent to the Cyp1A1 element (27). This cis-acting element is distinct from the negative regulatory element described for the CYP1A1 5Ј-flanking region by Hines and co-workers (59,60).…”

Section: Table Imentioning

confidence: 82%

“…The inhibitory region located between Ϫ210 and Ϫ432 also contained the minor start site (Ϫ332), two XREs, an E-box, and a putative SP-1 site (18-base G-rich sequence, G 6 TG 6 TG 4 ). A negative cis-acting regulatory element has been identified for the Cyp1A1 gene in rat epidermal cells (27). This is associated with differentiation at high passage numbers concomitant with down-regulation of Cyp1A1 and Cyp1B1 (27).…”

Section: Table Imentioning

confidence: 99%

“…A negative cis-acting regulatory element has been identified for the Cyp1A1 gene in rat epidermal cells (27). This is associated with differentiation at high passage numbers concomitant with down-regulation of Cyp1A1 and Cyp1B1 (27). A sequence similar to half of this element is found in the mouse Cyp1B1 region immediately downstream of the enhancer element in a position equivalent to the Cyp1A1 element (27).…”

Section: Table Imentioning

confidence: 99%

“…This effect is attributed to removal of labile repressor proteins that bind close to certain XREs (25). Distinct elements also provide additional negative trans-acting effects that may be specific to the cell type or growth state of the cells (26,27).…”

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confidence: 99%

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Characterization of the Mouse Cyp1B1 Gene

Zhang

Savas

Alexánder

et al. 1998

Journal of Biological Chemistry

124

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Transcriptional activation of the Cyp1B1 gene in rodents is stimulated by both polycyclic hydrocarbons and cAMP. The mouse Cyp1B1 gene structure contains three exons, of which the second nucleotide of exon 2 is the translation start site. Primer extension analysis identified a transcription start domain defining an exon 1 of 371 base pairs. The sequence 1.075 kilobases upstream of the transcription start site showed 11 xenobiotic-responsive elements (XRE) (T n GCGTG or GCGTG) that are putative aryl hydrocarbon receptor (AhR)-binding sites and three steroidogenic factor-1 motifs that are associated with cAMP-mediated transcriptional activation of genes. A transiently transfected Cyp1B1-luciferase construct, composed of exon 1 and 1.075 kilobases of 5-flanking region, was induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10.0 ؎ 3.0-fold, n ‫؍‬ 6) in C3H10T1/2 cells, which exclusively express Cyp1B1. The 90-base pair basal promoter contains two SP-1 sites, one SF-1 site, and a TATA-like box. TCDD induction and basal expression were dependent on positive regulatory elements present between ؊1075 and ؊810. Five XRE motifs localized in the enhancer region were completely conserved between mouse and human CYP1B1 sequences. Similar inductions were seen in Hepa-1 cells, which express Cyp1A1 but not Cyp1B1. However, basal Cyp1B1 promoter activities were 4 -10-fold higher in C3H10T1/2 cells providing the enhancer region was present, partially reproducing the in vivo cell-specific expression of Cyp1B1. Gel shift experiments established that TCDD stimulates AhR binding to the downstream XRE in the enhancer region. However, oligonucleotides that encompass two other XREs show a high affinity complex of similar size that is evident even without TCDD treatment and that does not contain either the AhR or AhR nuclear translocator. The fourth XRE is immediately adjacent to an E-box, and this oligonucleotide formed a smaller complex that was dependent on this E-box sequence. Negative regulatory sequences have been located between the promoter and TCDDresponsive enhancer regions. Constitutive expression of the Cyp1B1 gene was lost in AhR-deficient cells and was restored by transfected AhR cDNA. Reporter constructs function in a parallel manner, demonstrating the key role of the AhR in constitutive as well as TCDD-induced expression of Cyp1B1 in mouse embryo fibroblasts.

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Section: Table Imentioning

confidence: 82%

Section: Table Imentioning

confidence: 99%

Section: Table Imentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of the Mouse Cyp1B1 Gene

Zhang

Savas

Alexánder

et al. 1998

Journal of Biological Chemistry

124

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“…Our studies clearly demonstrated that the TCDD-dependent induction of Cyp1a-1 was suppressed in these tumors but not the adjacent normal epidermis. Recent studies from Denison's laboratory suggest that CYP1A1 induction in rat keratinocytes is modulated by the interaction of a trans-acting factor or factors with a negative regulatory element proximal to the CYP1A1 transcription start site [34]. Whereas processes initiated at this element suppress CYP1A1 induction, they do not disrupt ligand-induced AHR transformation or DRE binding [34].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of aryl hydrocarbon receptor function and cytochrome P450 1A1 induction by expression of ha-ras oncogenes

Reiners¹,

Jones²,

Hong³

et al. 1997

Mol. Carcinog.

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The immortalized human epithelial cell line MCF10A has the phenotypic characteristics of normal breast cells. Exposure of MCF10A cultures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stimulated the transcriptional activation of cytochrome P450 1A1 (CYP1A1), and CYP1B1, and NAD(P)H:quinone oxidoreductase. Northern blot hybridization and nuclear run-on assays demonstrated that transcriptional activation of these genes was suppressed in stably transfected cultures expressing an Ha-ras oncogene (the MCF10A-NeoT line). Similar suppression did not occur in stably transfected lines carrying the expression vector or a normal c-Ha-ras protooncogene. Western blot analyses and immunofluorescence microscopy demonstrated that the lack of inducibility in MDF10A-NeoT cells reflected neither reductions in aryl hydrocarbon receptor (AHR) and aryl hydrocarbon nuclear translocator protein nor prevention of TCDD-induced AHR translocation to the nucleus. Suppression did correlate with reductions in DNA-AHR complex formation, as analyzed by gel retardation assays of soluble cell extracts treated in vitro with TCDD. The induction of Cyp1a-1 by TCDD was also analyzed in transgenic mice that expressed a v-Ha-ras oncogene exclusively in their keratinocytes. Relative to littermates lacking the transgene, the induction of Cyp1a-1 by TCDD was partially suppressed (about 50%) in the epidermises of v-Ha-ras-positive transgenic mice. However, normal levels of Cyp1a-1 induction occurred in the livers of the same mice. induction of Cyp1a-1 by TCDD was also suppressed (more than 98%) in chemically induced skin papillomas having Ha-ras mutations, relative to uninvolved surrounding skin. These studies suggest that the p21-ras protein controls signal transduction pathways capable of modulating AHR function.

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Analysis of the Aryl Hydrocarbon Receptor (AhR) Signal Transduction Pathway

et al. 2002

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Analysis of the Ah Receptor Signal Transduction Pathway (Michael S. Denison, Jane M. Rohers, S. Renee Rushing. Carol L. Jones, Selwyna C. Tetangico, and Sharon Heath-Pagliuso, University of California, Davis, California).The protocols in this unit will allow researchers to detect the Ah receptor and characterize its functional activities (i.e., ligand binding, transformation and DNA binding, and gene expression) in their biological test system and to use these methods to detect chemical and biochemical events that affect this signaling system.

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Identification of a Novel Cis-acting Negative Regulatory Element Affecting Expression of the CYP1A1 Gene in Rat Epidermal Cells

Abstract: Polycyclic aromatic hydrocarbons such as 3-methylcholanthrene are toxic to rat epidermal cells in low passages (3 to 6), but cultures of high passage ( 15)

Cited by 27 publications

References 58 publications

Characterization of the Mouse Cyp1B1 Gene

Characterization of the Mouse Cyp1B1 Gene

Downregulation of aryl hydrocarbon receptor function and cytochrome P450 1A1 induction by expression of ha-ras oncogenes

Analysis of the Aryl Hydrocarbon Receptor (AhR) Signal Transduction Pathway

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