Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Hebbring, Scott J.; Chai, Yubo; Ji, Yuan; Abo, Ryan; Jenkins, Gregory D.; Fridley, Brooke L.; Zhang, Jianping; Eckloff, Bruce W.; Wieben, Eric D.; Weinshilboum, Richard M.

doi:10.1111/j.1471-4159.2012.07646.x

Cited by 36 publications

(32 citation statements)

References 35 publications

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“…SHMT enzymes catalyze the conversion of serine to glycine by catalyzing the transfer of the b-carbon of serine to tetrahydrofolate (THF) generating 5,10-methylene-THF and glycine (30,31). Phosphoglycerate dehydrogenase (PHGDH), another enzyme in the pathway of generating glycine from glucose, was recently shown to be amplified in melanoma (32) and breast cancer (33) and the next enzyme in this pathway, phosphoserine aminotransferase, is overexpressed in colorectal cancers, associated with chemoresistance (34), and required for serine pathway flux in breast cancer (33).…”

Section: Discussionmentioning

confidence: 99%

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Lee¹,

Haverty²,

Li³

et al. 2014

Cancer Research

132

106

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Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n ¼ 392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of-function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes. Subsequent functional assays identified SHMT2, a key enzyme in the serine/glycine synthesis pathway, as necessary for tumor cell survival but insufficient for transformation. The 26S proteasomal subunit, PSMB4, was identified as the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo. Elevated expression of SHMT2 and PSMB4 was found to be associated with poor prognosis in human cancer, supporting the development of molecular therapies targeting these genes or components of their pathways. Cancer Res; 74(11); 3114-26. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Lee¹,

Haverty²,

Li³

et al. 2014

Cancer Research

132

106

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“…Among the six proteins included in that analysis, GNMT, MAT1A, and BHMT are expressed predominantly in adult human liver, whereas COMT and SHMT1 are ubiquitously expressed. In a previous analysis of methionine and folate cycle mRNA expression in the Human Variation Panel lymphoblastoid cell lines that were used as a source of DNA for our gene resequencing studies (Hebbring et al, 2012), we observed strong correlations among mRNA expression levels for SHMT1, SHMT2, COMT, MAT2A, and MAT2B (Hebbring et al, 2012). Unfortunately, MAT1A, GNMT, and BHMT are not expressed in lymphoblastoid FIG.…”

Section: Discussionmentioning

confidence: 78%

Human Liver Methionine Cycle:MAT1AandGNMTGene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation

et al. 2012

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ABSTRACT:The "methionine cycle" plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p ‫؍‬ 3.9 ؋ 10 ؊10 ) and rs11752813 (corrected p ‫؍‬ 1.8 ؋ 10 ؊5 ), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p ‫؍‬ 1.5 ؋ 10 ؊3) and between GNMT and betaine homocysteine methyltransferase (p ‫؍‬ 1.6 ؋ 10 ؊7 ). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the "coordinate regulation" of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.

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“…This study indicated that low AGL expressing cells rely upon glucose to help drive increased glycine synthesis (9). This evidence was supported by the amplified serine hydroxymethyltransferase 2 (SHMT2) gene, responsible for glycine synthesis (13,14). In addition, elevated expression of SHMT2 correlates with poor patient prognosis in bladder cancer patients with low AGL expression, verifying the importance of glycine synthesis in AGL low bladder cancer (9).…”

Section: Agl Glycogen Metabolism and Regulation Of Glycine Synthesismentioning

confidence: 74%

Involvement of glycogen debranching enzyme in bladder cancer

Weinhaus

Guin

2017

Biomedical Reports

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Abstract. Bladder cancer is the most common malignancy of the urinary system, however the molecular pathways underlying this disease are incompletely understood. To understand new regulators of bladder cancer progression, the authors carried out a functional genomic screen which identified glycogen debranching enzyme (AGL) as a novel regulator of bladder cancer growth. Glycogen debranching enzyme is involved in glycogen breakdown and germline loss of function mutation of this gene leads to glycogen storage disease type III. To the best of the authors' knowledge, the present study is the first to demonstrate that loss of AGL leads to aggressive bladder tumor growth. AGL mRNA and protein expression in bladder tumors serve as a prognostic marker for patients. Interestingly, AGL's participation in regulating tumor growth is independent of its enzymatic function and involvement with glycogen metabolism in general. Detailed metabolomics and transcriptomic analysis indicated that increases in glucose metabolism, glycine synthesis driven by serine hydroxymethyltransferase 2 and increases in hyaluronic acid synthase 2-driven HA synthesis are major contributors of aggressive bladder tumor growth with loss of AGL. However, the detailed mechanism of how AGL regulates the above mentioned metabolic and genetic pathways is unknown and is being investigated. The present review focuses on AGL's involvement in bladder cancer.

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Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Cited by 36 publications

References 35 publications

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes

Human Liver Methionine Cycle:MAT1AandGNMTGene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation

Involvement of glycogen debranching enzyme in bladder cancer

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