HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis.

Vázquez-Chantada M, Fernández-Ramos D, Embade N, Martínez-Lopez N, Varela-Rey M, Woodhoo A, Luka Z, Wagner C, Anglim PP, Finnell RH, Caballería J, Laird-Offringa IA, Gorospe M, Lu SC, Mato JM, Martínez-Chantar ML
Gastroenterology. 2010 138 (5): 1943-53

PMID: 20102719 · PMCID: PMC2860011 · DOI:10.1053/j.gastro.2010.01.032

BACKGROUND & AIMS - Hepatic de-differentiation, liver development, and malignant transformation are processes in which the levels of hepatic S-adenosylmethionine are tightly regulated by 2 genes: methionine adenosyltransferase 1A (MAT1A) and methionine adenosyltransferase 2A (MAT2A). MAT1A is expressed in the adult liver, whereas MAT2A expression primarily is extrahepatic and is associated strongly with liver proliferation. The mechanisms that regulate these expression patterns are not completely understood.

METHODS - In silico analysis of the 3' untranslated region of MAT1A and MAT2A revealed putative binding sites for the RNA-binding proteins AU-rich RNA binding factor 1 (AUF1) and HuR, respectively. We investigated the posttranscriptional regulation of MAT1A and MAT2A by AUF1, HuR, and methyl-HuR in the aforementioned biological processes.

RESULTS - During hepatic de-differentiation, the switch between MAT1A and MAT2A coincided with an increase in HuR and AUF1 expression. S-adenosylmethionine treatment altered this homeostasis by shifting the balance of AUF1 and methyl-HuR/HuR, which was identified as an inhibitor of MAT2A messenger RNA (mRNA) stability. We also observed a similar temporal distribution and a functional link between HuR, methyl-HuR, AUF1, and MAT1A and MAT2A during fetal liver development. Immunofluorescent analysis revealed increased levels of HuR and AUF1, and a decrease in methyl-HuR levels in human livers with hepatocellular carcinoma (HCC).

CONCLUSIONS - Our data strongly support a role for AUF1 and HuR/methyl-HuR in liver de-differentiation, development, and human HCC progression through the posttranslational regulation of MAT1A and MAT2A mRNAs.

Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (34)

3' Untranslated Regions Animals Antigens, Surface Binding Sites Cell Differentiation Cell Proliferation Cells, Cultured Cell Transformation, Neoplastic ELAV-Like Protein 1 ELAV Proteins Gene Expression Regulation, Developmental Gene Expression Regulation, Enzymologic Gestational Age Glycine N-Methyltransferase Half-Life Hepatocytes Heterogeneous-Nuclear Ribonucleoprotein D Humans Liver Neoplasms Male Methionine Adenosyltransferase Methylation Mice Mice, Inbred C57BL Rats Rats, Wistar RNA, Messenger RNA-Binding Proteins RNA Interference RNA Processing, Post-Transcriptional RNA Stability S-Adenosylmethionine Signal Transduction Transfection

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