| Added by | mollevi |
|---|---|
| Last modified by | celine.gongora |
| Group name | EquipeCG |
| Item Type | Journal Article |
| Title | Characterization of a novel PXR isoform with potential dominant-negative properties |
| Creator | Breuker et al. |
| Author | C. Breuker |
| Author | C. Planque |
| Author | F. Rajabi |
| Author | J. C. Nault |
| Author | G. Couchy |
| Author | J. Zucman-Rossi |
| Author | A. Evrard |
| Author | J. Kantar |
| Author | E. Chevet |
| Author | P. Bioulac-Sage |
| Author | J. Ramos |
| Author | E. Assenat |
| Author | D. Joubert |
| Author | J. Pannequin |
| Author | F. Hollande |
| Author | J. M. Pascussi |
| Abstract | BACKGROUND & AIMS: The nuclear Pregnane X Receptor (PXR, NR1I2) plays a pivotal role in xenobiotic metabolism. Here, we sought to characterize a new PXR isoform (hereafter called small PXR or sPXR) stemming from alternative transcription starting sites downstream of a CpG Island located near exon 3 of the human PXR gene. METHODS: Quantitative RT-PCR, western blot, methylation-specific PCR, luciferase reporter assays, electro-mobility shift assays, and stable sPXR overexpression were used to examine sPXR expression and function in hepatocellular cell lines, healthy human liver (n=99), hepatocellular adenomas (HCA, n=91) and hepatocellular carcinoma samples (HCC, n=213). RESULTS: Liver sPXR mRNA expression varied importantly among individuals and encodes a 37kDa nuclear protein consisting of the ligand-binding domain of PXR that behaves as a dominant-negative of PXR transactivation properties. In vitro methylation of the sPXR upstream promoter abolished its activity, while the demethylation agent 5-aza-2-deoxycytidine increased sPXR mRNA expression in several cell lines. Finally, we observed that sPXR mRNA expression displayed significant differences related to HCA or HCC biology. CONCLUSIONS: This novel PXR isoform, displaying a dominant-negative activity and regulated by DNA methylation, is associated with outcomes of patients with HCC treated by resection, suggesting that it represents a key modulator of PXR. |
| Publication | J Hepatol |
| Volume | 61 |
| Pages | 609-16 |
| Date | Sep 2014 |
| Journal Abbr | Journal of hepatology |
| DOI | 10.1016/j.jhep.2014.04.030 |
| ISSN | 1600-0641 (Electronic) 0168-8278 (Linking) |
| Tags | original |
| Date Added | 2018/07/20 - 10:05:58 |
| Date Modified | 2019/05/14 - 13:57:07 |
| Notes and Attachments | (Note) (Note) 24798619 (Attachment) |
Institut de Recherche en Cancérologie de
