Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation

Pañeda, Covadonga; Gorospe, Itziar; Herrera, Blanca; Nakamura, Toshikazu; Fabregat, Isabel; Varela-Nieto, Isabel

doi:10.1053/jhep.2002.32538

Cited by 38 publications

(39 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Others have shown that MAT2A up-regulation is required for proliferation to occur (22). Northern and Western blot analyses show that MAT1A expression remains elevated up to 72 h after PH in mice (Fig.…”

Section: Mat Expression During Liver Regenerationmentioning

confidence: 73%

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

et al. 2004

View full text Add to dashboard Cite

Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor κB (NFκB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFκB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wildtype mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals. ethionine is an essential amino acid metabolized mainly by the liver, where it is converted, by the enzyme methionine adenosyltransferase (MAT), into Sadenosylmethionine (SAMe), the main biological methyl donor, precursor for polyamines and GSH (1). About 50% of methionine metabolism and up to 85% of all methylation reactions occur in the liver (2). In mammals, there are two genes encoding MAT isoenzymes: MAT I/III are gene products of MAT1A, and MAT II is the gene product of MAT2A. Whereas MAT1A is expressed mainly in the adult liver and is a marker for differentiated liver, MAT2A is expressed in all tissues, including fetal liver, hepatocellular carcinoma (HCC), and, in small quantities, in the adult liver (2). MAT2A is up-regulated during rapid liver growth and dedifferentiation (2). Due to differences in the regulatory and kinetic properties of the various MATs, MAT II cannot maintain the same high levels of SAMe as compared with the combination of MAT I and MAT III (2). Consequently, in MAT1A knockout mice, despite a significant increase in MAT2A expression, the liver content of SAMe is reduced about threefold from birth, when the switch from MAT2A and MAT1A normally takes place (3).It has long been re...

show abstract

Section: Mat Expression During Liver Regenerationmentioning

confidence: 73%

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

et al. 2004

View full text Add to dashboard Cite

show abstract

“…A strong relationship between HCC and MAT has been reported. As mentioned in the literature, a switch in gene expression from MAT1A to MAT2A, known as the MAT1A:MAT2A switch, has been found in liver cancer [8]–[11]. The MAT1A:MAT2A switch, which was accompanied with an increasing expression of MAT2B, results in decreasing SAM levels and facilitates cancer cell growth [2], [4], [6], [12], [13], [15].…”

Section: Discussionmentioning

confidence: 99%

“…Because MAT isoforms differ in catalytic kinetics and regulatory properties, MAT1A-expressing cells have considerably higher SAM levels than do MAT2A-expressing cells [6], [7]. In hepatocellular carcinoma (HCC), the down-regulation of MAT1A gene and the up-regulation of MAT2A occur, known as the MAT1A:MAT2A switch [8]–[11]. The switch results in lower SAM contents, which provide a growth advantage to hepatoma cells [2], [4], [6], [12], [13].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

2013

View full text Add to dashboard Cite

Methionine adenosyltransferase (MAT) is the cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM), the principal biological methyl donor and a key regulator of hepatocyte proliferation, death and differentiation. Two genes, MAT1A and MAT2A, encode 2 distinct catalytic MAT isoforms. A third gene, MAT2B, encodes a MAT2A regulatory subunit. In hepatocellular carcinoma (HCC), MAT1A downregulation and MAT2A upregulation occur, known as the MAT1A:MAT2A switch. The switch is accompanied with an increasing expression of MAT2B, which results in decreased SAM levels and facilitates cancer cell growth. Berberine, an isoquinoline alkaloid isolated from many medicinal herbs such as Coptis chinensis, has a wide range of pharmacological effects including anti-cancer effects. Because drug-induced microRNAs have recently emerged as key regulators in guiding their pharmacological effects, we examined whether microRNA expression is differentially altered by berberine treatment in HCC. In this study, we used microRNA microarrays to find that the expression level of miR-21-3p (previously named miR-21*) increased after berberine treatment in the HepG2 human hepatoma cell line. To predict the putative targets of miR-21-3p, we integrated the gene expression profiles of HepG2 cells after berberine treatment by comparing with a gene list generated from sequence-based microRNA target prediction software. We then confirmed these predictions through transfection of microRNA mimics and a 3′ UTR reporter assay. Our findings provide the first evidence that miR-21-3p directly reduces the expression of MAT2A and MAT2B by targeting their 3′ UTRs. In addition, an overexpression of miR-21-3p increased intracellular SAM contents, which have been proven to be a growth disadvantage for hepatoma cells. The overexpression of miR-21-3p suppresses growth and induces apoptosis in HepG2 cells. Overall, our results demonstrate that miR-21-3p functions as a tumor suppressor by directly targeting both MAT2A and MAT2B, indicating its therapeutic potential in HCC.

show abstract

“…SAM-dependent methylation has been shown to be central to many biological processes and the steady-state SAM level has been accepted as a critical marker of the genomic methylation status (12,13). In hepatocytes, SAM level is related to the differentiation status of the cells, being high in quiescent hepatocytes and low in proliferating hepatocytes (14)(15)(16). SAM is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferase (MAT).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Induces Genomic DNA Demethylation through the Activation of HIF-1α and Transcriptional Upregulation of MAT2A in Hepatoma Cells

Liu

Zhao

et al. 2011

Molecular Cancer Therapeutics

131

110

View full text Add to dashboard Cite

Hypoxia-inducible factor 1 (HIF-1) emerges as a crucial player in tumor progression. However, its role in hepatocellular carcinoma (HCC), especially its relation with global DNA methylation patterns in HCC under hypoxic tumor microenvironment is not completely understood. Methionine adenosyltransferase 2A (MAT2A) maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status. In this study, we investigated the link between HIF-1a and MAT2A as a mechanism responsible for the change in genomic DNA methylation patterns in liver cancer under hypoxia conditions. Our results showed that hypoxia induces genomic DNA demethylation in CpG islands by reducing the steady-state SAM level both in vitro and in vivo. In addition, HIF-1a and MAT2A expression is correlated with tumor size and TNM stage of liver cancer tissues. We further showed that hypoxia-induced MAT2A expression is HIF-1a dependent and requires the recruitment of p300 and HDAC1. We also identified an authentic consensus HIF1a binding site in MAT2A promoter by site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Taken together, we show for the first time that hypoxia induces genomic DNA demethylation through the activation of HIF-1a and transcriptional upregulation of MAT2A in hepatoma cells. These findings provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC. Mol Cancer Ther; 10(6); 1113-23. Ó2011 AACR.

show abstract

Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation

Cited by 38 publications

References 49 publications

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

Hypoxia Induces Genomic DNA Demethylation through the Activation of HIF-1α and Transcriptional Upregulation of MAT2A in Hepatoma Cells

Contact Info

Product

Resources

About