Dephosphorylation of Sp1 at Ser-59 by Protein Phosphatase 2A (PP2A) is required for induction of CYP1A1 transcription after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or omeprazole

Shimoyama, Shuji; Kasai, Shuya; Kahn-Perlès, Brigitte; Kikuchi, Hideaki

doi:10.1016/j.bbagrm.2013.12.004

Cited by 15 publications

(17 citation statements)

References 36 publications

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“…Nevertheless, our study showed that the promoter region of CYP1A1 contains three functional regions one proximal (-62 to -47) and two distal (-987 to -976 and -952 to -935) regions consistent with the results of a previous study reporting that an XRE sequence existed upstream of human CYP1A1 [53]. Both TCDD and omeprazole induced CYP1A1 transcription via the dephosphorylation of Sp1 at Ser-59 by PP2A [27]. In addition, the binding of Sp1 to the proximal promoter region of CYP3A4 has been shown [22], and Sp1 regulated both the basal and rifampin (RIF)-mediated transcription of porcine CYP3A46 by binding to its related cis-regulatory element in the proximal promoter and distal enhancer [56].…”

Section: Discussionsupporting

confidence: 91%

“…Sp1 and AhR/Arnt heterodimers bind to the Sp1‐like motif and XRE, respectively, and enhance the constitutive and inducible transcriptional activities of human CYP1B1 . Gut‐enriched Krüppel‐like factor inhibits Sp1‐mediated activation of the CYP1A1 promoter in Chinese hamster ovary cells , and TCDD induces CYP1A1 transcription via protein phosphatase 2A (PP2A)‐mediated dephosphorylation of Sp1 at Ser‐59 . However, the relationship between Sp1 and AhR in mediating the basal expression of CYP1A1 has not been systematically clarified.…”

Section: Introductionmentioning

confidence: 99%

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AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1

Chen

et al. 2019

The FEBS Journal

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Cytochrome P450 1A1 (CYP1A1) is abundant in the kidney, liver, and intestine and is involved in the phase I metabolism of numerous endogenous and exogenous compounds. Therefore, exploring the regulatory mechanism of its basal expression in humans is particularly important to understand the bioactivation of several procarcinogens to their carcinogenic derivatives. Site‐specific mutagenesis and deletion of the transcription factor binding site determined the core cis‐acting elements in the human CYP1A1 proximal and distal promoter regions. The proximal promoter region [overlapping xenobiotic‐responsive element (XRE) and GC box sequences] determined the basal expression of CYP1A1. In human hepatocellular carcinoma cells (HepG2) with aryl hydrocarbon receptor (AhR) or specificity protein 1 (Sp1) knockdown, we confirmed that AhR and Sp1 are involved in basal CYP1A1 expression. In HepG2 cells overexpressing either AhR or Sp1, AhR determined the proximal transactivation of basal CYP1A1 expression. Via DNA affinity precipitation assays and ChIP, we found that AhR bound to the promoter and recruited Sp1 to transactivate CYP1A1 expression. The coordinated interaction between Sp1 and AhR was identified to be DNA mediated. Our work revealed a basal regulatory mechanism of an interesting human gene by which AhR interacts with Sp1 through DNA and recruits Sp1 to regulate basal CYP1A1 expression.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1

Chen

et al. 2019

The FEBS Journal

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“…The amino acid sequence for Sp1 in pigs and humans has more than 90% identity similarity, leading us to believe that Sp1 might have a conserved regulatory function in CYP1A1 expression. In humans, Sp1 activates the CYP1A1 promoter ( Zhang et al, 1998 ), and phosphorylation of Sp1 regulates CYP1A1 expression ( Shimoyama et al, 2014 ). We also found that the GC box at the proximal promoter of p CYP1A1 is the main cis -element that plays a regulatory role by recruiting Sp1.…”

Section: Discussionmentioning

confidence: 99%

Sp1, Instead of AhR, Regulates the Basal Transcription of Porcine CYP1A1 at the Proximal Promoter

Xie

Jiang

et al. 2018

Front. Pharmacol.

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Pigs are commonly used as an animal model to evaluate the toxic effects of exogenous compounds. Cytochrome P450 1A1 (CYP1A1) metabolizes numerous exogenous compounds and is abundantly expressed in the liver, kidneys, and intestines. The high amino acid similarity between human and porcine CYP1A1 indicates that they probably have the same metabolic characteristics. Therefore, understanding the regulatory mechanism of CYP1A1 expression in pigs is particularly important for predicting the toxicology and metabolic kinetics of exogenous chemicals. Currently, the transcriptional regulation of porcine CYP1A1 has rarely been studied, especially regarding basal transcription. In this study, we first confirmed that the key regulatory elements of porcine CYP1A1 basal transactivation are in the proximal promoter region using promoter truncation analysis via a dual luciferase assay in a porcine kidney cell line LLC-PK1. Two overlapping cis-elements, the xenobiotic response element (XRE) and GC box, in this proximal region potentially play key roles in the basal transactivation of porcine CYP1A1. Furthermore, using electrophoretic mobility shift assay and chromatin immunoprecipitation, the GC box binding protein Sp1 was confirmed to bind to the proximal promoter of porcine CYP1A1, instead of AhR, the XRE binding protein. In LLC-PK1 cells, by knocking down either Sp1 or AhR, the expression of porcine CYP1A1 at the mRNA level and protein level was significantly downregulated, suggesting both proteins are important for porcine CYP1A1 expression. However, promoter activity analysis in LLC-PK1 cells treated with an AhR agonist and antagonist confirmed that AhR does not participate in the basal regulation of porcine CYP1A1 at the proximal promoter. In conclusion, our study revealed that the proximal promoter is the key regulatory region for porcine CYP1A1 basal expression. Although AhR plays an important role in the transactivation of porcine CYP1A1 expression, the key determinant transcription factor for its basal transactivation is Sp1 at the proximal promoter of porcine CYP1A1.

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“…Whole-cell extracts were prepared as described previously [21]. BV-2 cells were seeded at a density of 1.0×10 5 cells/35-mm dish (for whole-cell extracts) or at a density of 1.0×10 6 cells/100-mm dish (for cell fractionation).…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-2

et al. 2019

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It has been reported that neuroinflammation occurs in the central nervous system (CNS) in patients with neuropathic pain, Alzheimer’s disease and autism spectrum disorder. The 18-kDa translocator protein TSPO is used as an imaging target in positron emission tomography to detect neuroinflammation, and its expression is correlated with microglial activation. However, the mechanism underlying the transcriptional regulation of Tspo induced by inflammation is not clear. Here, we revealed that lipopolysaccharide (LPS) -induced Tspo expression was activated by the AP-1 complex in a mouse microglial cell line, BV-2. Knockdown of c-Fos and c-Jun, the components of AP-1, reduced LPS-induced Tspo expression. Furthermore, the enrichment of Sp1 in the proximal promoter region of Tspo was increased in the presence of LPS. In addition, the binding of histone deacetylase 1 (HDAC1) to the enhancer region, which contains the AP-1 site, was decreased by LPS treatment, but there were no significant differences in HDAC1 binding to the proximal promoter region with or without LPS. These results indicated that HDAC1 is involved not in the proximal promoter region but in the enhancer region. Our study revealed that inflammatory signals induce the recruitment of AP-1 to the enhancer region and Sp1 to the proximal promoter region of the Tspo gene and that Sp1 may regulate the basal expression of Tspo.

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Dephosphorylation of Sp1 at Ser-59 by Protein Phosphatase 2A (PP2A) is required for induction of CYP1A1 transcription after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or omeprazole

Cited by 15 publications

References 36 publications

AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1

AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1

Sp1, Instead of AhR, Regulates the Basal Transcription of Porcine CYP1A1 at the Proximal Promoter

Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-2

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