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Gene Review

Slc19a1  -  solute carrier family 19 (folate...

Mus musculus

Synonyms: AI323572, Folate transporter 1, IFC-1, Intestinal folate carrier 1, RFC, ...
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Disease relevance of Slc19a1

  • At 38 weeks, RFC1(+/-) mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1(+/+) mice [1].
  • In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development [1].
  • It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity [2].
  • Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed [2].
  • L1210 leukemia cells transport reduced folates and methotrexate via a well defined reduced folate carrier system and, in the absence of low folate selective pressure, do not express an alternate endocytotic route mediated by cell surface folate receptors [3].

High impact information on Slc19a1


Chemical compound and disease context of Slc19a1


Biological context of Slc19a1


Anatomical context of Slc19a1


Associations of Slc19a1 with chemical compounds

  • This was evidenced by the increase in Vmax for [3H]MTX (methotrexate) influx and a commensurate increase in the amount of the 46 kilodalton (kDa) transport protein and reduced folate carrier (RFC-1) mRNA [8].
  • The concentrative advantage for RFC1 (the ratio of [MTX]i in MTXrA-R16 to L1210 cells) increased from 1.8 at 0.1 microM MTX to 3.8 at an [MTX]e level of 30 microM [15].
  • Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs [11].
  • In an ongoing study of structure-function relationships of the murine reduced folate carrier 1 (RFC1), a glutamate to lysine mutation at amino acid 45 was identified in a methotrexate (MTX)-resistant L1210 clonal variant in which MTX and 5-formyltetrahydrofolate (5-CHO-THF) influx was markedly decreased [16].
  • The data suggest that substitution of a positive for a negative amino acid at position 45 results in the loss of RFC1 mobility in the absence of small inorganic anions that bind to, and neutralize the positive charge on, the lysine residue [16].

Regulatory relationships of Slc19a1

  • FR-alpha expressed at sufficient levels can mediate influx of MTX and folates into cells at rates comparable to the reduced folate carrier and hence has pharmacologic and physiologic importance [3].
  • RESULTS: In the mouse, RFC transcripts and protein are expressed in the E10.0 placenta and yolk sac [14].

Other interactions of Slc19a1

  • The data indicate that resistance to pemetrexed in the MTA-13 cell line was due to changes in both RFC and FPGS expression, two proteins that act in tandem to regulate polyglutamation of folates and antifolates in cells, resulting in cellular depletion of these active pemetrexed congeners [12].
  • The present work demonstrates that RFC is present in placenta and yolk sac and provides the first evidence that it is expressed in the neural tube, craniofacial region, limb buds and heart during organogenesis [14].

Analytical, diagnostic and therapeutic context of Slc19a1


  1. Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis. Ma, D.W., Finnell, R.H., Davidson, L.A., Callaway, E.S., Spiegelstein, O., Piedrahita, J.A., Salbaum, J.M., Kappen, C., Weeks, B.R., James, J., Bozinov, D., Lupton, J.R., Chapkin, R.S. Cancer Res. (2005) [Pubmed]
  2. Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies. Spiegelstein, O., Gould, A., Wlodarczyk, B., Tsie, M., Lu, X., Le, C., Troen, A., Selhub, J., Piedrahita, J.A., Salbaum, J.M., Kappen, C., Melnyk, S., James, J., Finnell, R.H. Toxicol. Appl. Pharmacol. (2005) [Pubmed]
  3. Distinguishing between folate receptor-alpha-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. Spinella, M.J., Brigle, K.E., Sierra, E.E., Goldman, I.D. J. Biol. Chem. (1995) [Pubmed]
  4. Rosette-forming ability of thymus-derived lymphocytes in cell-mediated immunity. I. Delayed hypersensitivity and in vitro cytotoxicity. Elliott, B.E., Haskill, J.S., Axelrad, M.A. J. Exp. Med. (1975) [Pubmed]
  5. Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. Zhao, R., Gao, F., Goldman, I.D. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  6. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Wang, E.S., O'Connor, O., She, Y., Zelenetz, A.D., Sirotnak, F.M., Moore, M.A. Leuk. Lymphoma (2003) [Pubmed]
  7. Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells. Zhao, R., Gao, F., Wang, Y., Diaz, G.A., Gelb, B.D., Goldman, I.D. J. Biol. Chem. (2001) [Pubmed]
  8. Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter. Roy, K., Chiao, J.H., Spengler, B.A., Tolner, B., Yang, C.H., Biedler, J.L., Sirotnak, F.M. Cancer Genet. Cytogenet. (1998) [Pubmed]
  9. Characterization of a mutation in the reduced folate carrier in a transport defective L1210 murine leukemia cell line. Brigle, K.E., Spinella, M.J., Sierra, E.E., Goldman, I.D. J. Biol. Chem. (1995) [Pubmed]
  10. Structure and regulation of the murine reduced folate carrier gene: identification of four noncoding exons and promoters and regulation by dietary folates. Liu, M., Ge, Y., Cabelof, D.C., Aboukameel, A., Heydari, A.R., Mohammad, R., Matherly, L.H. J. Biol. Chem. (2005) [Pubmed]
  11. Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs. Zhao, R., Russell, R.G., Wang, Y., Liu, L., Gao, F., Kneitz, B., Edelmann, W., Goldman, I.D. J. Biol. Chem. (2001) [Pubmed]
  12. Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line. Wang, Y., Zhao, R., Goldman, I.D. Biochem. Pharmacol. (2003) [Pubmed]
  13. RFC-1 gene expression regulates folate absorption in mouse small intestine. Chiao, J.H., Roy, K., Tolner, B., Yang, C.H., Sirotnak, F.M. J. Biol. Chem. (1997) [Pubmed]
  14. Reduced-folate carrier (RFC) is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart. Maddox, D.M., Manlapat, A., Roon, P., Prasad, P., Ganapathy, V., Smith, S.B. BMC Dev. Biol. (2003) [Pubmed]
  15. Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. Zhao, R., Seither, R., Brigle, K.E., Sharina, I.G., Wang, P.J., Goldman, I.D. J. Biol. Chem. (1997) [Pubmed]
  16. A mutated murine reduced folate carrier (RFC1) with increased affinity for folic acid, decreased affinity for methotrexate, and an obligatory anion requirement for transport function. Zhao, R., Assaraf, Y.G., Goldman, I.D. J. Biol. Chem. (1998) [Pubmed]
  17. Role of the amino acid 45 residue in reduced folate carrier function and ion-dependent transport as characterized by site-directed mutagenesis. Zhao, R., Gao, F., Wang, P.J., Goldman, I.D. Mol. Pharmacol. (2000) [Pubmed]
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