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Series GSE60684 Query DataSets for GSE60684
Status Public on Aug 24, 2014
Title Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors (mRNA)
Organism Mus musculus
Experiment type Expression profiling by array
Summary The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcino- genesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARKO -PXRKO ), double humanized CAR and PXR (CARh - PXRh), and wild-type C57BL/6 mice. Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar tran- scriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were ob- served with peak expression occurring between 1 and 7 days PB ex- posure. All these transcriptional responses were absent in CARKO- PXRKO mouse livers and largely reversible in wild-type and CARh - PXRh mouse livers following 91 days of PB exposure and a subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARh-PXRh mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
 
Overall design 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
 
Contributor(s) Luisier R, Lempiäinen H, Scherbichler N, Braeuning A, Geissler M, Dubost V, Müller A, Scheer N, Chibout S, Hara H, Picard F, Theil D, Couttet P, Vitobello A, Grenet O, Grasl-Kraupp B, Ellinger-Ziegelbauer H, Thomson JP, Meehan RR, Elcombe CR, Henderson CJ, Wolf CR, Schwarz M, Moulin P, Terranova R, Moggs JG
Citation(s) 24690595
Submission date Aug 22, 2014
Last update date Feb 11, 2019
Contact name Jonathan Moggs
E-mail jonathan.moggs@novartis.com
Organization name Novartis
Street address Fabrikstrasse 2
City Basel
ZIP/Postal code 4056
Country Switzerland
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (167)
GSM1484841 group2, Phenobarbital wild-type 2022
GSM1484842 group2, Phenobarbital wild-type 2023
GSM1484843 group2, Phenobarbital wild-type 2024
This SubSeries is part of SuperSeries:
GSE60693 Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors
GSE68387 IMI MARCAR Project: towards novel biomarkers for cancer risk assessment
Relations
BioProject PRJNA259291

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Supplementary file Size Download File type/resource
GSE60684_RAW.tar 584.0 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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