Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA312150 | ENA |
REPOSITORIES: ENA
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Project description:[Abstract] The R653Q variant in the synthetase domain of the folate-metabolizing enzyme MTHFD1 has been shown to increase risk for birth defects, but it does not affect risk for development of colorectal cancer (CRC). However, since we have shown that this variant reduces purine synthesis, the goal of this study was to determine whether it could affect tumor growth. Using our mouse model for MTHFD1-synthetase deficiency (Mthfd1S+/-), we induced tumor formation with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S+/- mice. Tumor size was significantly smaller due to mutant genotype, particularly in males. Tumor size was increased in female mice compared with males, regardless of genotype. Tumor number was not influenced by genotype and was lower in females. Inflammation within tumors of male Mthfd1S+/- mice was lower than in wild-type mice. Proliferation of mouse embryonic fibroblasts from mutant lines was slower than that in wild-type fibroblasts. Gene expression analysis in tumor adjacent normal (preneoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) or inflammation (Atf3, Saa1, TNF-α) that were downregulated in mutant male mice. Female mutants did not have changes in expression for those genes, nor in tumor inflammation levels, compared with wild-type, suggesting a different mechanism directing tumor growth in females. We suggest that restriction of purine synthesis and reduced expression of critical tumor-promoting genes leads to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant.
2017-03-01 | GSE77931 | GEO
Project description:The metabolic pathways that underlie the association between folate deficiency and increased risk for colorectal cancer (CRC) remain unclear. We have studied the effect of C1THF synthase (encoded by the Mthfd1 gene) and dietary folate and choline on intestinal tumor development in Apcmin/+ mice and azoxymethane (AOM)-induced colon cancer in mice. Mthfd1 deficiency did not alter tumor number or load in Apcmin/+ mice, but did result in a decreased incidence of colon tumors. Conversely, Mthfd1 deficiency increased tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. Here we tested colons isolated from wildtype and Mthfd1-deficient animals for alterations in gene expression. Keywords: genetic modification RNA was isolated from proximal colons of MTHFD heterozygous and wild-type mice raised on a control diet. Three colon samples were isolated from each genotype to provide biological replication.
2010-03-20 | E-GEOD-15419 | biostudies-arrayexpress
Project description:The metabolic pathways that underlie the association between folate deficiency and increased risk for colorectal cancer (CRC) remain unclear. We have studied the effect of C1THF synthase (encoded by the Mthfd1 gene) and dietary folate and choline on intestinal tumor development in Apcmin/+ mice and azoxymethane (AOM)-induced colon cancer in mice. Mthfd1 deficiency did not alter tumor number or load in Apcmin/+ mice, but did result in a decreased incidence of colon tumors. Conversely, Mthfd1 deficiency increased tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. Here we tested colons isolated from wildtype and Mthfd1-deficient animals for alterations in gene expression. Keywords: genetic modification
2010-03-20 | GSE15419 | GEO
Project description:Folate metabolism provides the building blocks of many classes of biomolecules including purine nucleotides, thymidylate, serine and methionine and is an important target of antimetabolite drugs. A central enzyme in the pathway is the trifunctional MTHFD1, that catalyzes the interconversion of folates by its formyltetrahydrofolate synthetase and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase domains. Here, we employ large-scale chemical and genome-wide genetic screens to investigate the chemical and genetic dependencies caused by MTHFD1 loss-of-function and uncover a central role of the enzyme in balancing the response to extracellular adenosine. We show that adenosine is essential in MTHFD1KO cells, where adenine-containing compounds counter AMPK activation and increase proliferation in a PARP8, ATF7 and PML-dependent manner. In contrast, adenosine supplementation causes strong toxicity in patient-derived MTHFD1-derived cells harboring dehydrogenase/cyclohydrolase domain mutations. This response, mediated by replication stress and activation of the DNA damage response, is dependent on the nucleotide salvage enzyme HRPT1 and on NUDT5, an enzyme involved in nuclear ATP generation. Our findings suggest an evolutionary rationale for integrating three distinct enzymatic activities within the single MTHFD1 protein and propose the application of dehydrogenase/cyclohydrolase inhibitors in tumors located in an adenosine-rich microenvironment.
2023-04-26 | GSE201334 | GEO
Project description:TLR4 deficiency attenuates kidney injury after ischemic reperfusion as measured by both renal function and morphology. To better understand the role of TLR4 during the acute kidney injury, we used DNA microarray to identify genes that were differentially expressed on kidneys in wildtype B10 mice and TLR4 null mice during the early stage of injury. A murine ischemic reperfusion injury model was established. After right nephrectomy, the left pedicle was clamped for 23min followed by 4hr reperfusion. Sham mice were used as controls. 6 WT males and 6 TLR4 null males were included with 3 ischemic and 3 shams in each group.
2012-08-15 | E-GEOD-34351 | biostudies-arrayexpress
Project description:Dynamic tumor growth patterns in a novel murine model of colorectal cancer
| PRJNA201326 | ENA
Project description:In order to further investigate silencing mechanisms, we screened a mutagenized Arabidopsis thaliana population for expression of SDCpro-GFP, redundantly controlled by DNA methyltransferases DRM2 and CMT3. We identified the hypomorphic mutant mthfd1-1, carrying a mutation (R175Q) in the cytoplasmic bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (MTHFD1). Accumulation of homocysteine and S-adenosylhomocysteine, genome-wide DNA hypomethylation, loss of H3K9me, and transposon derepression indicate that S-adenosylmethionine-dependent transmethylation is inhibited in mthfd1-1.
2016-06-07 | GSE77966 | GEO
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for functional regulators and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | GSE105786 | GEO
Project description:TET2 deficiency subverts tumor immunity [model 3]
| PRJNA851067 | ENA
Project description:Targeting Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth
| PRJNA347480 | ENA