Characterization of adjacent E‐box and nuclear factor 1‐like DNA binding sequence in the human <i>CYP1A2</i> promoter

Narvaez, Marta J.; Anderson, Garret R.; Pickwell, George V.; Quattrochi, Linda C.

doi:10.1002/jbt.20063

Cited by 13 publications

(13 citation statements)

References 37 publications

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“…The interplay between HNF1-alpha and USF1/2 has been previously shown to be implicated in the liver-specific expression of the pyruvate kinase gene, in the regulation of three human class I alcohol dehydrogenase genes and in the constitutive expression of CYP1A2 [43-45]. Considering that UGT1A1-mediated glucuronidation is the primary route of irinotecan inactivation, it was suggested that the level of UGT1A1 expression might contribute to the differential chemosensitivity of colon tumors [46-48].…”

Section: Discussionmentioning

confidence: 99%

Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells

et al. 2010

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BackgroundUDP-glucuronosyltransferase 1A1 (UGT1A1) is a pivotal enzyme involved in metabolism of SN-38, the active metabolite of irinotecan commonly used to treat metastatic colorectal cancer. We previously demonstrated aberrant methylation of specific CpG dinucleotides in UGT1A1-negative cells, and revealed that methylation state of the UGT1A1 5'-flanking sequence is negatively correlated with gene transcription. Interestingly, one of these CpG dinucleotides (CpG -4) is found close to a HNF1 response element (HRE), known to be involved in activation of UGT1A1 gene expression, and within an upstream stimulating factor (USF) binding site.ResultsGel retardation assays revealed that methylation of CpG-4 directly affect the interaction of USF1/2 with its cognate sequence without altering the binding for HNF1-alpha. Luciferase assays sustained a role for USF1/2 and HNF1-alpha in UGT1A1 regulation in colon cancer cells. Based on the differential expression profiles of HNF1A gene in colon cell lines, we also assessed whether methylation affects its expression. In agreement with the presence of CpG islands in the HNF1A promoter, treatments of UGT1A1-negative HCT116 colon cancer cells with a DNA methyltransferase inhibitor restore HNF1A gene expression, as observed for UGT1A1.ConclusionsThis study reveals that basal UGT1A1 expression in colon cells is positively regulated by HNF1-alpha and USF, and negatively regulated by DNA methylation. Besides, DNA methylation of HNF1A could also play an important role in regulating additional cellular drug metabolism and transporter pathways. This process may contribute to determine local inactivation of drugs such as the anticancer agent SN-38 by glucuronidation and define tumoral response.

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Section: Discussionmentioning

confidence: 99%

Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells

et al. 2010

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“…The expression of CYP1A2 is mainly hepatic-specific. Several transcription factors have been implicated as regulators of the constitutive and tissue-specific expression of CYP1A2, including members of the nuclear factor 1 family of transcription factors (Narvaez et al, 2005) and the liver-enriched transcription factor HNF1 (Chung and Bresnick, 1997). Moreover, DNA binding sequences of several putative regulatory factors have also been characterized, including activator protein-1 element (Quattrochi et al, 1998) and multiple E-box motifs (Narvaez et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Several transcription factors have been implicated as regulators of the constitutive and tissue-specific expression of CYP1A2, including members of the nuclear factor 1 family of transcription factors (Narvaez et al, 2005) and the liver-enriched transcription factor HNF1 (Chung and Bresnick, 1997). Moreover, DNA binding sequences of several putative regulatory factors have also been characterized, including activator protein-1 element (Quattrochi et al, 1998) and multiple E-box motifs (Narvaez et al, 2005). However, the organization of the CYP1A cluster on chromosome 15, in which a common 23.3-kb sequence separates CYP1A1 and CYP1A2, suggests the possibility that distal regulatory elements may be shared (Corchero et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation ofCYP2C9,CYP1A1, andCYP1A2by Hepatocyte Nuclear Factor 4α Requires Coactivators Peroxisomal Proliferator Activated Receptor-γ Coactivator 1α and Steroid Receptor Coactivator 1

Martínez-Jiménez

Castell²,

Gómez-Lechón³

et al. 2006

Mol Pharmacol

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Hepatocyte nuclear factor 4␣ (HNF4␣) is a key transcription factor for the constitutive expression of cytochromes P450 (P450s) in the liver. However, human hepatoma HepG2 cells show a high level of HNF4␣ but express only marginal P450 levels. We found that the HNF4␣-mediated P450 transcription in HepG2 is impaired by the low level of coactivators peroxisomal proliferator activated receptor-␥ coactivator 1␣ (PGC1␣) and steroid receptor coactivator 1 (SRC1). Reporter assays with a chimeric CYP2C9-LUC construct demonstrated that the sole transfection of coactivators induced luciferase activity in HepG2 cells. In HeLa cells however, CYP2C9-LUC activity only significantly increased when coactivators were cotransfected with HNF4␣. A deletion mutant lacking the two proximal HNF4␣ binding sites in the CYP2C9 promoter did not respond to PGC1␣ or SRC1, demonstrating that coactivators were acting through HNF4␣ response elements. Adenovirus-mediated transfection of PGC1␣ in human hepatoma cells caused a significant dose-dependent increase in CYP2C9, CYP1A1, and CYP1A2 and in the positive control CYP7A1. PGC1␣ also showed a moderate activating effect on CYP3A4, CYP3A5, and CYP2D6. Adenoviral transfection of SRC1 had a lessened effect on P450 genes. Chromatin immunoprecipitation assay demonstrated in vivo binding of HNF4␣ and PGC1␣ to HNF4␣ response sequences in the CYP2C9 promoter and to three new regulatory regions in the common 23.3 kilobase spacer sequence of the CYP1A1/2 cluster. Insulin treatment of HepG2 and human hepatocytes caused repression of PGC1␣ and a concomitant down-regulation of P450s. Our results establish the importance of coactivators PGC1␣ and SRC1 for the hepatic expression of human P450s and uncover a new HNF4␣-dependent regulatory mechanism to constitutively control the CYP1A1/2 cluster.Cytochromes P450 (P450s) are a superfamily of monooxygenases that play a key role in the detoxification of xenobiotics, the metabolic activation of chemical carcinogens, and the oxidative metabolism of endogenous compounds such as steroids, fatty acids, and prostaglandins. Most foreign compound-metabolizing P450s are highly expressed in the liver, although lower levels of particular P450 forms are also found in extrahepatic tissues such as intestine, lung, and kidney. The molecular mechanism sustaining the hepatic-specific P450 expression is not completely understood, although recent studies have shown that P450 expression in the liver is primarily governed at the transcriptional level and relies on the combinatorial action of a set of liver-enriched transcription factors such as C/EBP␣, C/EBP␤, HNF1␣, HNF3␥, and

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“…Detailed studies of regulation of transcription have shown that NF1 can function either as an activator or as a repressor [26]. Thus, NF1 affects a broad range of biological activities: a) cell differentiation in embryogenesis [27]; b) regulation of proteins involved in cell-cell (28) and cell-extracellular matrix interactions important in epithelial-mesenchymal transition (EMT) [28]; c) participation in the regulation of environmental stress genes CYP1A1 [29], CYP1A2 [30], CYP2A3 [31]; d) regulation of expression of mitochondrial adenine nucleotide translocator-2 gene (ANT2), indicating the possibility that NF1 might be involved in the regulation of cell energy metabolism [32]; e) cell cycle regulation and growth arrest due to transcription regulation of genes encoding cyclin D [33], GAAD153 [34], p53 [35] and p21 [36].…”

Section: Participation Of Nf1 Proteins In Various Cell Functionsmentioning

confidence: 99%

New insights into the role of NF1 in cancer

Sabová

Kretova²,

Luciaková³

2013

neo

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NF1 proteins are a family of transcription factors that act either as repressors or as activators. Functional studies indicate that NF1 participate in signaling pathways that regulate cell viability, proliferation and differentiation. Participation in regulation of genes important for tumor progression and metastasizing suggests a potential value of NF1 as a prognostic factor for certain types of cancer.

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Characterization of adjacent E‐box and nuclear factor 1‐like DNA binding sequence in the human CYP1A2 promoter

Cited by 13 publications

References 37 publications

Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells

Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells

Transcriptional Activation ofCYP2C9,CYP1A1, andCYP1A2by Hepatocyte Nuclear Factor 4α Requires Coactivators Peroxisomal Proliferator Activated Receptor-γ Coactivator 1α and Steroid Receptor Coactivator 1

New insights into the role of NF1 in cancer

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