TY - JOUR
T1 - HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis
AU - Vázquez-Chantada, Mercedes
AU - Fernández-Ramos, David
AU - Embade, Nieves
AU - Martínez-Lopez, Nuria
AU - Varela-Rey, Marta
AU - Woodhoo, Ashwin
AU - Luka, Zigmund
AU - Wagner, Conrad
AU - Anglim, Paul P.
AU - Finnell, Richard H.
AU - Caballería, Juan
AU - Laird-Offringa, Ite A.
AU - Gorospe, Myriam
AU - Lu, Shelly C.
AU - Mato, José M.
AU - Martínez-Chantar, M. Luz
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
KW - AUF1
KW - HuR
KW - MAT1A
KW - MAT2A
UR - http://www.scopus.com/inward/record.url?scp=77951696468&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951696468&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2010.01.032
DO - 10.1053/j.gastro.2010.01.032
M3 - Article
C2 - 20102719
AN - SCOPUS:77951696468
SN - 0016-5085
VL - 138
SP - 1943-1953.e3
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -