HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis

Mercedes Vázquez-Chantada, David Fernández-Ramos, Nieves Embade, Nuria Martínez-Lopez, Marta Varela-Rey, Ashwin Woodhoo, Zigmund Luka, Conrad Wagner, Paul P. Anglim, Richard H. Finnell, Juan Caballería, Ite A. Laird-Offringa, Myriam Gorospe, Shelly C. Lu, José M. Mato, M. Luz Martínez-Chantar

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Abstract

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.

Original languageEnglish (US)
JournalGastroenterology
Volume138
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

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Methionine Adenosyltransferase
Carcinogenesis
Liver
S-Adenosylmethionine
Hepatocellular Carcinoma
Biological Phenomena
Messenger RNA
RNA-Binding Proteins

Keywords

  • AUF1
  • HuR
  • MAT1A
  • MAT2A

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Vázquez-Chantada, M., Fernández-Ramos, D., Embade, N., Martínez-Lopez, N., Varela-Rey, M., Woodhoo, A., ... Martínez-Chantar, M. L. (2010). HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis. Gastroenterology, 138(5). https://doi.org/10.1053/j.gastro.2010.01.032

HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis. / Vázquez-Chantada, Mercedes; Fernández-Ramos, David; Embade, Nieves; Martínez-Lopez, Nuria; Varela-Rey, Marta; Woodhoo, Ashwin; Luka, Zigmund; Wagner, Conrad; Anglim, Paul P.; Finnell, Richard H.; Caballería, Juan; Laird-Offringa, Ite A.; Gorospe, Myriam; Lu, Shelly C.; Mato, José M.; Martínez-Chantar, M. Luz.

In: Gastroenterology, Vol. 138, No. 5, 05.2010.

Research output: Contribution to journalArticle

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 2010, 'HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis', Gastroenterology, vol. 138, no. 5. https://doi.org/10.1053/j.gastro.2010.01.032
Vázquez-Chantada M, Fernández-Ramos D, Embade N, Martínez-Lopez N, Varela-Rey M, Woodhoo A et al. HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis. Gastroenterology. 2010 May;138(5). https://doi.org/10.1053/j.gastro.2010.01.032
Vázquez-Chantada, Mercedes ; Fernández-Ramos, David ; Embade, Nieves ; Martínez-Lopez, Nuria ; Varela-Rey, Marta ; Woodhoo, Ashwin ; Luka, Zigmund ; Wagner, Conrad ; Anglim, Paul P. ; Finnell, Richard H. ; Caballería, Juan ; Laird-Offringa, Ite A. ; Gorospe, Myriam ; Lu, Shelly C. ; Mato, José M. ; Martínez-Chantar, M. Luz. / HuR/Methyl-HuR and AUF1 Regulate the MAT Expressed During Liver Proliferation, Differentiation, and Carcinogenesis. In: Gastroenterology. 2010 ; Vol. 138, No. 5.
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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

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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

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