The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

Ifergan, Ilan; Jansen, Gerrit; Assaraf, Yehuda G.

doi:10.1074/jbc.m802812200

Cited by 43 publications

(30 citation statements)

References 57 publications

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“…This lack of association with US population can be attributed to folate fortification program in the USA. SLC19A1 expression was reported to be downregulated in conditions of folate deprivation (Ifergan et al 2008) suggesting that availability of folate might act as an effect modifier. Decreased transcription and altered function might have deleterious impact, thus influencing intracellular folate levels.…”

Section: Discussionmentioning

confidence: 99%

Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk

et al. 2016

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Aberrations in one-carbon metabolism were reported to increase breast cancer risk by influencing the DNA synthesis and methylation of DNA and catecholamines. However, the results of these association studies remain inconclusive. We have explored the contribution of eight genetic polymorphisms in modulating the susceptibility to breast cancer by performing a meta-analysis of worldwide studies. In total, 62 case-control studies representing 17 different populations involving 18,117 breast cancer cases and 23,573 healthy controls were included in this meta-analysis. Out of the eight polymorphisms analyzed, methylenetetrahydrofolate reductase (MTHFR) C677T exhibited positive association with the breast cancer risk in both fixed effects (OR 1.14, 95 % CI 1.10-1.17) and random effects (OR 1.10, 95 % CI 1.02-1.18) models. Solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A exhibited positive association (OR 1.16, 95 % CI 1.03-1.31) while MTR A2756G exhibited an inverse association (OR 0.78, 95 % CI 0.75-0.82) with the breast in fixed effect model alone. Significant heterogeneity was observed in the association of MTHFR C677T with breast cancer even between studies from the same geographical area, specifically among Chinese, Indians, and Turks. Subgroup analysis revealed MTHFR C677T-mediated breast cancer risk in post-menopausal women and women with low dietary intake of folate. Geographical area wise segregation of data revealed MTHFR-mediated increased breast cancer risk in populations who consume methionine-rich diet. Altitude-level variations were observed in the association of SHMT1 C1420T with breast cancer. India and Brazil of same altitude showed an inverse association with this polymorphism, while USA and China that share similar altitude showed a null association. MTHFR C677T and SLC19A1 G80A are the two polymorphisms of one-carbon metabolic pathway that increase breast cancer in the worldwide population. Dietary patterns and altitudinal variations are the likely risk modulators that are contributing toward ethnic-and population-level variations in genetic associations.

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Section: Discussionmentioning

confidence: 99%

Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk

et al. 2016

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“…The SAM/SAH ratio, homocysteine concentration, specific dietary factors (especially folate and methionine), vitamin B 12 , and vitamin B 6 are all important determinants of one-carbon metabolism and the metabolic balance between the remethylation and transsulfuration pathways (2). Humans consume many more methyl groups than are gained from dietary methionine.…”

Section: Metabolic Regulation Of Remethylation and Transsulfuration Pmentioning

confidence: 99%

“…Folate polyglutamate species with up to 4 glutamate residues can be ejected from the cell in 3 different ways: via multidrug resistance protein family members (MRPs/ ABCCs), breast cancer resistance protein family members (BRCP/ABCG2), and RFCs. The first 2 are adenosine triphosphate (ATP)-dependent and downregulated in folate deficiency (12).…”

Section: Cellular and Intracellular Transportmentioning

confidence: 99%

“…Folate and vitamin B 12 are independent and essential components of onecarbon metabolism (25). Deficiency in vitamin B 12 , which is also a cofactor for methionine synthase, also leads to a functional deficiency in folate and plays a role as another cofactor of the same enzyme. On the other hand, low folate concentrations cause reductions in neurotransmitter synthesis, SAM synthesis, and the methylation of phospholipids in neuronal membranes.…”

Section: Relationship Between One-carbon Metabolism and Neurologicalmentioning

confidence: 99%

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Folate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry

Coşar¹,

İpçioğlu²,

Özcan³

et al. 2014

Turk J Med Sci

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This work aims to study recent climatic oscillations and their influence on sedimentation in the Ria de Vigo, a coastal embayment in Galicia, NW Spain. It is based on the study of clay mineral assemblages, in conjunction with other proxies (granulometric, geochemical, geochronological and microfaunal), in the core KSGX 24. A Benthic Foraminifera High Productivity (BFHP) proxy was used to determine changes in the flux of organic matter (OM) at the bottom of the study area. Total organic carbon (TOC) content is not a suitable proxy to estimate changes in the past supply of OM due to diagenetic processes. The sedimentation was finest in 3 sections: ~ 230-214 cm, ~ 185-73 cm and ~ 20-0 cm. These muddy sections are characterised, in general, by higher proportions of detrital minerals, concentrations of several chemical elements related to lithogenic sources and BFHP values. In addition, these sections are impoverished in carbonates, Ca, Sr and La when compared with the layers with the highest sand content. The clay mineral assemblage of the studied site, characterised by the dominance of illite, intermediate concentrations of kaolinite and minor amounts of smectite and chlorite, reveals the prevalence of a typical temperate humid climate in the last 3 ka BP, the estimated age for the core base. However, the quantities of illite and chlorite increase in the muddy layers. The characteristics of these muddy layers were interpreted as representing relatively cold climatic oscillations associated with the strengthening of northerly winds and the prevalence of an upwelling regime corresponding to well-known periods, such as the first cold period of the Upper Holocene (~ 2.9 ka cal BP), the Dark Ages (between ~ 2.2 -1.2 ka cal BP) and the Little Ice Age (~ 0.6 ka cal BP).

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“…33 In addition, RFC-1 also plays an important role in folate homeostasis where it gets down-regulated in response to folate deficiency. 34 The gene is highly polymorphic and has been found to be associated with different diseases like ischemic stroke, neural tube defects and different types of cancers.…”

mentioning

confidence: 99%

Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

Mirgal

Ghosh²,

Mahanta

et al. 2016

Trans R Soc Trop Med Hyg

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Background: Recent studies in experimental mice have shown that mild deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme confers protection against malaria, thus providing an important basis for the hypothesis that MTHFR polymorphism, i.e. C677T, might have been subjected to selection pressure against malaria. The present study was undertaken in a malaria endemic region in North East India to assess whether a similar selection advantage exists for other genes in folate metabolism pathway.Methods: A total of 401 subjects including 131 symptomatic malaria, 97 asymptomatic malaria and 173 normal healthy controls were analysed for nine polymorphisms (single-nucleotide polymorphisms [SNPs] in eight genes and insertion/deletion in one gene): MTHFR C677T, methionine synthase reductase (MTRR) A66G, glutamate carboxypeptidase II (GCPII) C1561T, cystathionine beta-synthase (CBS) 844ins68, reduced folate carrier-1 (RFC-1) G80A, serine hydroxymethyltransferase (SHMT) C1420T, methionine synthase (MTR) A2756G, MTHFR G1793A (D 919G), glycine N-methyltransferase (GNMT) 1289 by PCR-RFLP technique. Differences in frequencies of genotype distribution of each polymorphic marker between these groups were evaluated.Results: MTRR A2756G, SHMT C1420T, GCPII C1561T, MTRR A2756G and GNMT C1289T and RFC1 G80A polymorphisms showed significantly different prevalence between different groups analyzed. No significant differences were seen in the distribution of other polymorphisms. Conclusions:The study gives a clue for the possible selection of specific polymorphisms in the genes involved in the folate metabolism pathway by malaria parasite.

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The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

Cited by 43 publications

References 57 publications

Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk

Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk

Folate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry

Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

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