Heterogeneous Nuclear Ribonucleoprotein A1 and Regulation of the Xenobiotic-Inducible Gene<i>Cyp2a5</i>

Raffalli-Mathieu, Françoise; Glisovic, Tina; Ben‐David, Yaacov; Lang, Matti A.

doi:10.1124/mol.61.4.795

Cited by 31 publications

(21 citation statements)

References 30 publications

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“…The evidence of Cyp2a5 mRNA stabilization was first reported by Aida and Negishi (Aida and Negishi, 1991;Hahnemann et al, 1992). Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a multifunctional protein involved in transcriptional regulation and cell growth, has been identified as the RNA-binding protein responsible for the Cyp2a5 mRNA stabilization (Tilloy-ellul et al, 1999;Raffalli-Mathieu et al, 2002). These studies have shown that hnRNA1 functions as an mRNA stabilizing trans-acting factor on the 3' UTR, and also acts as a transcriptional activator by interacting with the proximal promoter (Tilloy-ellul et al, 1999;Raffalli-Mathieu et al, 2002;Glisovic et al, 2003).…”

Section: Post-transcriptional Regulation Of Cyp2a5mentioning

confidence: 93%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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Section: Post-transcriptional Regulation Of Cyp2a5mentioning

confidence: 93%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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“…Previous studies have shown that regulation of CYP2A5 by pyrazole occurs post-transcriptionally via mRNA stabilization (Hahnemann et al, 1992). Electrophoretic mobility shift assays have shown that pyrazole increases binding of the heterogeneous nuclear ribonucleoprotein A1 to a cis-acting element in the 3Ј-UTR of CYP2A5 mRNA, suggesting a key regulatory role (Raffalli-Mathieu et al, 2002). It is unclear whether these mRNA protein interactions are increased in conditions that alter cellular redox status.…”

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confidence: 99%

Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Gilmore¹,

Kirby²

2003

J Pharmacol Exp Ther

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Murine hepatic cytochrome P450 2A5 (CYP2A5) is uniquely induced by a variety of agents that cause liver injury and inflammation, conditions that are typically associated with downregulation of P450s. We hypothesized that induction of CYP2A5 occurs in response to hepatocellular damage resulting in endoplasmic reticulum (ER) stress. Treatment of mice in vivo and mouse hepatocytes in primary culture with the CYP2A5 inducer pyrazole resulted in overexpression of the ER stress biomarker glucose-regulated protein (GRP) 78. Treatment of primary hepatocytes with ER stress activators thapsigargin, tunicamycin, and trans-4,5-dihydroxy-1,2-dithiane (DTT ox ) and the calcium ionophore A23187 (calcimycin) resulted in elevated GRP78 mRNA levels; however, only the reducing agent DTT ox induced levels of CYP2A5 mRNA, protein, and coumarin 7-hydroxylase activity. To test the hypothesis that CYP2A5 induction is due to liver injury resulting from altered cellular redox status, we demonstrated that CYP2A5 induction, elevated serum alanine aminotransferase, and oxidative protein damage occur concurrently in pyrazole-treated mice. Pyrazole also induced the expression of cytosolic ␣ and class glutathione S-transferase expression both in vivo and in primary mouse hepatocytes. Moreover, treatment of hepatocytes with the redox cycling quinone menadione resulted in overexpression of CYP2A5 and GSTM1 mRNA. Finally, pretreatment of hepatocytes with the antioxidants N-acetylcysteine and vitamin E attenuated pyrazole-mediated increases in CYP2A5 mRNA levels. These findings clearly indicate that induction of mouse hepatic CYP2A5 during liver injury occurs via a novel mechanism involving ER stress due to altered cellular redox status.

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“…A comparative UV cross-linking experiment revealed that the 34-/37-kDa complex formed with the human CYP2A6 3Ј-UTR was indistinguishable in size (data not shown), with the major complex found to bind to the CYP2A5 3Ј-UTR using mouse liver extracts (Geneste et al, 1996;Raffalli-Mathieu et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…Increased mRNA half-life is mediated by interaction of the RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) A1 with a putative hairpin loop in the 3Ј-untranslated region (UTR) of CYP2A5 transcript (TilloyEllul et al, 1999;Raffalli-Mathieu et al, 2002;Glisovic et al, 2003a). hnRNPA1 probably plays a major role in the stabilization of CYP2A5 mRNA occurring in response to toxic chemicals, for the maintenance of constant CYP2A5 mRNA levels during conditions of impaired transcription (Glisovic et al, 2003b), and it may contribute to CYP2A5 up-regulation in pathological conditions (Raffalli-Mathieu et al, 2002). Whether similar regulation mechanisms apply to the close human ortholog CYP2A6 is unknown.…”

mentioning

confidence: 99%

Interaction of Heterogeneous Nuclear Ribonucleoprotein A1 with Cytochrome P450 2A6 mRNA: Implications for Post-Transcriptional Regulation of theCYP2A6Gene

Christian

Lang²,

Maurel³

et al. 2004

Mol Pharmacol

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The human xenobiotic-metabolizing enzyme cytochrome P450, CYP2A6, catalyzes the bioactivation of a number of carcinogens and drugs and is overexpressed in cases of liver diseases, such as cirrhosis, viral hepatitis, and parasitic infestation, and in certain tumor cells. This suggests that CYP2A6 may be a major liver catalyst in pathological conditions. In the present study, we have addressed molecular mechanisms underlying the regulation of the CYP2A6 gene. We present evidence of several proteins present in human hepatocytes that interact specifically with the 3Ј-untranslated region (UTR) of CYP2A6 mRNA. Biochemical and immunological evidence show that the RNAprotein complex of highest intensity contains the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 or a closely related protein. Mapping of the hnRNP A1 binding site within CYP2A6 3Ј-UTR reveals that the smallest portion of RNA supporting significant binding consists of 111 central nucleotides of the 3Ј-UTR. Our studies also indicate that hnRNPA1 from HepG2 cancer cells exhibits modified binding characteristics to the CYP2A6 3Ј-UTR compared with primary hepatocytes. We found that the level of CYP2A6 mRNA remains high in conditions of impaired transcription in primary human hepatocytes, showing that CYP2A6 expression can be affected post-transcriptionally in conditions of cellular stress. Our results indicate that the post-transcriptional regulation involves interaction of the hnRNP A1 protein with CYP2A6 mRNA. The present data suggest that hnRNPA1 is a critical regulator of expression of the human CYP2A6 gene and support the notion that this P450 isoform may be of particular significance in stressed human liver cells.

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Heterogeneous Nuclear Ribonucleoprotein A1 and Regulation of the Xenobiotic-Inducible GeneCyp2a5

Cited by 31 publications

References 30 publications

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Interaction of Heterogeneous Nuclear Ribonucleoprotein A1 with Cytochrome P450 2A6 mRNA: Implications for Post-Transcriptional Regulation of theCYP2A6Gene

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