Role of Methionine Adenosyltransferase 2A and S-adenosylmethionine in Mitogen-Induced Growth of Human Colon Cancer Cells

Chen, Hui; Xia, Meng; Lin, Mark T.; Yang, Heping; Kuhlenkamp, John; Li, Tony; Sodir, Nicole M.; Chen, Yong Heng; Josef-Lenz, Heinz; Laird, Peter W.; Clarke, Steven; Mato, José M.; Lu, Shelly C.

doi:10.1053/j.gastro.2007.03.114

Cited by 89 publications

(160 citation statements)

References 33 publications

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“…Cellular and extracellular SAMe, MTA, and SAH levels were measured by high-performance liquid chromatography as described. 28 Nuclear Protein Extraction and Western Blot Analysis. Nuclear extracts were prepared as described 30 and resolved by electrophoresis on 7%-12% sodium dodecyl sulfate-polyacrylamide gel.…”

Section: Methodsmentioning

confidence: 99%

“…MTA has been shown to block methylation of H3K4 in a number of systems. [23][24][25]27 In contrast to MTA, which is a very stable molecule, its precursor SAMe is highly unstable and can be converted to MTA spontaneously and also via the polyamine pathway 27,28 ; this suggests that the effect of exogenous SAMe may be mediated by MTA. It is also known that MTA inhibits SAH hydrolase, 32 the enzyme responsible for metabolizing SAH, and SAH itself is a strong inhibitor of almost all SAMe-dependent methyltransferases.…”

Section: Methodsmentioning

confidence: 99%

“…23,24 In several studies, its ability to decrease the H3K4 methylation was correlated with attenuation of gene expression. 25,26 In contrast to MTA, which is a very stable molecule, its precursor SAMe is highly unstable and can be converted to MTA spontaneously and also via the polyamine pathway, 27,28 and this suggests that the effect of exogenous SAMe may be mediated by MTA. In the present study, we examined whether the mechanism of SAMe's inhibitory effect might involve modulation of histone modifications and whether this might be mediated via MTA.…”

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S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

et al. 2008

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We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor ␣ (TNF␣) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNF␣ expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNF␣ promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPSmediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNF␣ and iNOS promoters. Conclusion: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation. (HEPATOLOGY 2008;47:1655-1666

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

et al. 2008

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“…For example, mutations involving the MAT1A gene have links with hepatic MAT deficiency which leads to hypermethioninemia (6,7). Expression of MATα2 confers a growth advantage in cells and is important for differentiation and apoptosis (1) in diseases such as human hepatocellular carcinoma (5), colon cancer (8), and leukemia (9).…”

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Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes

Murray

Antonyuk

Marina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The principal methyl donor of the cell, S-adenosylmethionine (SAMe), is produced by the highly conserved family of methionine adenosyltranferases (MATs) via an ATP-driven process. These enzymes play an important role in the preservation of life, and their dysregulation has been tightly linked to liver and colon cancers. We present crystal structures of human MATα2 containing various bound ligands, providing a "structural movie" of the catalytic steps. High-to atomic-resolution structures reveal the structural elements of the enzyme involved in utilization of the substrates methionine and adenosine and in formation of the product SAMe. MAT enzymes are also able to produce S-adenosylethionine (SAE) from substrate ethionine. Ethionine, an S-ethyl analog of the amino acid methionine, is known to induce steatosis and pancreatitis. We show that SAE occupies the active site in a manner similar to SAMe, confirming that ethionine also uses the same catalytic site to form the product SAE.methionine adenosyltransferase | cell growth | liver cancer | X-ray crystallography | methylation

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“…2) [1,26]. SAM, как уже отме-чалось, является основным донором биологической метильной группы для различных метилтрансфераз, что приводит к метилированию таких субстратов, как нуклеиновые кислоты (ДНК, РНК), белки и липиды [33], а также к синтезу малых молекул (например, креатина, фосфатидилхолина, адреналина), модифи-кации ксенобиотиков (например, тиолов, арсенита) и инактивации медиаторов (например, адренали-на, норадреналина, допамина) [34]. Метилирование ДНК является одной из основных эпигенетических модификаций генома, которая регулирует важные аспекты его функционирования как во время раз-вития, так и у взрослых организмов, в том числе импринтинг и X-хромосомную инактивацию [35].…”

Section: гомоцистеин и пути его превращенияunclassified

Homocysteine and Polyamines: Metabolic Relationship and Its Clinical Significance in Folate Inhibitors Chemotherapy

Неборак¹,

Лебедева²,

Головня³

et al. 2017

Oncopediatria

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Role of Methionine Adenosyltransferase 2A and S-adenosylmethionine in Mitogen-Induced Growth of Human Colon Cancer Cells

Cited by 89 publications

References 33 publications

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes

Homocysteine and Polyamines: Metabolic Relationship and Its Clinical Significance in Folate Inhibitors Chemotherapy

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