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Gene Review

FOLR1  -  folate receptor 1 (adult)

Homo sapiens

Synonyms: Adult folate-binding protein, FBP, FOLR, FR-alpha, Folate receptor 1, ...
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Disease relevance of FOLR1

  • Rous sarcoma virus (RSV) promoter-driven expression of the FR-alpha gene was 7 to 30 times greater in the FR-alpha-positive than in FR-alpha-negative cells, both at the protein and mRNA levels, independently of intron sequences [1].
  • Among 39 patients with spina bifida (SB), 47 mothers with a child with SB, and 10 controls, no polymorphism was present in the folate receptor alpha (FR-alpha) gene or in the folate receptor beta (FR-beta) gene [2].
  • Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells [3].
  • We studied the involvement of 11q markers in ovarian cancer by looking for tumour-specific loss of heterozygosity (LOH), as well as amplification or rearrangements that might explain the overexpression of FOLR1 [4].
  • The first crystal structure of the iron-transporter ferric ion-binding protein from Haemophilus influenzae (hFBP), at 1.6 A resolution, reveals the structural basis for iron uptake and transport required by several important bacterial pathogens [5].
  • FR alpha overexpression is unlikely secondary to the decreased RFC expression in osteosarcoma [6].

Psychiatry related information on FOLR1

  • Relative theta power was most sensitive for the differentiation of demented patients irrespective of type of normal controls (P < 0.01), whereas OCC/FR alpha ratio (occipital divided by frontal power) separated between dementia types (P < 0.01) as well as between DAT and normals (P < 0.05) [7].

High impact information on FOLR1

  • FR-alpha expression in Jurkat cells facilitated MBG or EBO entry, and FR-blocking reagents inhibited infection by MBG or EBO [8].
  • Finally, FR-alpha bound cells expressing MBG or EBO GP and mediated syncytia formation triggered by MBG GP [8].
  • Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans [9].
  • We have now measured the extent of energy transfer between isoforms of the folate receptor bound to a fluorescent analogue of folic acid, in terms of the dependence of fluorescence polarization on fluorophore densities in membranes [10].
  • IMPLICATIONS: The fact that folate receptor expression in these malignant cells can be manipulated using retinoids and steroids suggests that these hormones could modulate the efficiency of folate and antifolate uptake via the folate receptor and may enhance the usefulness of the receptor as a target for immunotherapy [11].

Chemical compound and disease context of FOLR1


Biological context of FOLR1


Anatomical context of FOLR1

  • Substitution of this FR-alpha element in FR-beta increased the in vivo degradation rate of the transcript in the nuclei of MG63 cells but not in the nuclei of HeLa cells or in the cytosol of MG63 or HeLa cells [1].
  • The present study, undertaken primarily to establish the isoform identity of the FR expressed in the placental syncytiotrophoblast, does not support this currently prevailing nomenclature [3].
  • Based on the tissue/cell type from which these isoforms have been cloned, it is currently believed that FR-alpha is the isoform expressed in adult tissues whereas FR-beta is the isoform expressed in fetal tissues including placenta [3].
  • A membrane-associated folate binding protein (FBP) and a soluble FBP, which is released into the culture medium, have been purified from human KB cells using affinity chromatography [19].
  • These studies indicate that the membrane FBP of KB cells contains covalently bound fatty acids that may serve to anchor the protein in the cell membrane [19].

Associations of FOLR1 with chemical compounds

  • Further studies of mutations in the 5'-UTR of FOLR1, and in particular of their interplay with folate intake status, are warranted [20].
  • One example is the cloning of the FOLR1 gene coding for the folate-binding protein (Folbp1), which has recently been inactivated in mice, thus representing an elegant model to investigate the consequence on the homocysteine metabolism [17].
  • Indeed, cell culture studies show that expression of the FRalpha gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations [21].
  • Thus, regardless of whether steps were taken to remove endogenous folates before receptor binding assays, FR on primitive hematopoietic cells failed to bind 3H-FA, fluorescein isothiocyanate (FITC)-linked FA, or FA-derivatized liposomes [22].
  • Modulation of the folate receptor type beta gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites [12].

Physical interactions of FOLR1


Enzymatic interactions of FOLR1

  • In particular, the p53 form of lyn appeared to be enriched and phosphorylated in the anti-folate receptor MOv19 monoclonal antibody immunoprecipitate, whereas a 40 kDa band common to anti-folate receptor and anti-lyn immunoprecipitates was the phosphorylated form of the G(&agr;)(i-3) subunit [25].

Co-localisations of FOLR1

  • The results indicate that in steady-state FR is not significantly colocalized with caveolin [26].

Regulatory relationships of FOLR1


Other interactions of FOLR1

  • Herein, we report a novel human FR cDNA (FR-P3) isolated from a placental library and the chromosomal organization of the human FR-P3 gene [18].
  • Sixteen-h exposure to CB300638 inhibited the rate of (3)H(2)O release from 5-[(3)H]dUrd (in situ TS assay) in A431, A431-FBP, and KB cells with IC(50) values of 0.1 microM, 0.005 microM, and 0.002 microM, respectively [32].
  • Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates [33].
  • More specific receptors like the folate receptor, IGF-II/Man-6-P receptor, and gp280/IFR, identical to the intrinsic factor receptor, are also functioning in the apical endocytic pathway of renal proximal tubules [34].
  • The alpha human folate receptor (alphahFR), or KB cell folate receptor, gene contains two major promoters that produce transcripts, KB1 and KB4, varying only in the length and sequence of their 5' untranslated regions (UTRs) [35].

Analytical, diagnostic and therapeutic context of FOLR1


  1. mRNA instability in the nucleus due to a novel open reading frame element is a major determinant of the narrow tissue specificity of folate receptor alpha. Zheng, X., Kelley, K., Elnakat, H., Yan, W., Dorn, T., Ratnam, M. Mol. Cell. Biol. (2003) [Pubmed]
  2. Molecular genetic analysis of human folate receptors in neural tube defects. Heil, S.G., van der Put, N.M., Trijbels, F.J., Gabreëls, F.J., Blom, H.J. Eur. J. Hum. Genet. (1999) [Pubmed]
  3. Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells. Prasad, P.D., Ramamoorthy, S., Moe, A.J., Smith, C.H., Leibach, F.H., Ganapathy, V. Biochim. Biophys. Acta (1994) [Pubmed]
  4. Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer. Foulkes, W.D., Campbell, I.G., Stamp, G.W., Trowsdale, J. Br. J. Cancer (1993) [Pubmed]
  5. Structure of Haemophilus influenzae Fe(+3)-binding protein reveals convergent evolution within a superfamily. Bruns, C.M., Nowalk, A.J., Arvai, A.S., McTigue, M.A., Vaughan, K.G., Mietzner, T.A., McRee, D.E. Nat. Struct. Biol. (1997) [Pubmed]
  6. The folate receptor alpha is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate. Yang, R., Kolb, E.A., Qin, J., Chou, A., Sowers, R., Hoang, B., Healey, J.H., Huvos, A.G., Meyers, P.A., Gorlick, R. Clin. Cancer Res. (2007) [Pubmed]
  7. Quantitative topographical EEG compared to FDG PET for classification of vascular and degenerative dementia. Szelies, B., Mielke, R., Herholz, K., Heiss, W.D. Electroencephalography and clinical neurophysiology. (1994) [Pubmed]
  8. Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses. Chan, S.Y., Empig, C.J., Welte, F.J., Speck, R.F., Schmaljohn, A., Kreisberg, J.F., Goldsmith, M.A. Cell (2001) [Pubmed]
  9. Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Piedrahita, J.A., Oetama, B., Bennett, G.D., van Waes, J., Kamen, B.A., Richardson, J., Lacey, S.W., Anderson, R.G., Finnell, R.H. Nat. Genet. (1999) [Pubmed]
  10. GPI-anchored proteins are organized in submicron domains at the cell surface. Varma, R., Mayor, S. Nature (1998) [Pubmed]
  11. Similarity of folate receptor expression in UMSCC 38 cells to squamous cell carcinoma differentiation markers. Orr, R.B., Kreisler, A.R., Kamen, B.A. J. Natl. Cancer Inst. (1995) [Pubmed]
  12. Modulation of the folate receptor type beta gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites. Hao, H., Qi, H., Ratnam, M. Blood (2003) [Pubmed]
  13. Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia. Wang, H., Zheng, X., Behm, F.G., Ratnam, M. Blood (2000) [Pubmed]
  14. Gene transfection and expression of the ovarian carcinoma marker folate binding protein on NIH/3T3 cells increases cell growth in vitro and in vivo. Bottero, F., Tomassetti, A., Canevari, S., Miotti, S., Ménard, S., Colnaghi, M.I. Cancer Res. (1993) [Pubmed]
  15. Growth of ovarian-carcinoma cell lines at physiological folate concentration: effect on folate-binding protein expression in vitro and in vivo. Miotti, S., Facheris, P., Tomassetti, A., Bottero, F., Bottini, C., Ottone, F., Colnaghi, M.I., Bunni, M.A., Priest, D.G., Canevari, S. Int. J. Cancer (1995) [Pubmed]
  16. Role of membrane folate-binding protein in the cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro. Sen, S., Erba, E., D'Incalci, M., Bottero, F., Canevari, S., Tomassetti, A. Br. J. Cancer (1996) [Pubmed]
  17. Recent insights into the molecular genetics of the homocysteine metabolism. Födinger, M., Wagner, O.F., Hörl, W.H., Sunder-Plassmann, G. Kidney Int. Suppl. (2001) [Pubmed]
  18. Expression of the human placental folate receptor transcript is regulated in human tissues. Organization and full nucleotide sequence of the gene. Page, S.T., Owen, W.C., Price, K., Elwood, P.C. J. Mol. Biol. (1993) [Pubmed]
  19. Purified membrane and soluble folate binding proteins from cultured KB cells have similar amino acid compositions and molecular weights but differ in fatty acid acylation. Luhrs, C.A., Pitiranggon, P., da Costa, M., Rothenberg, S.P., Slomiany, B.L., Brink, L., Tous, G.I., Stein, S. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  20. Novel mutations in the 5'-UTR of the FOLR1 gene. Börjel, A.K., Yngve, A., Sjöström, M., Nilsson, T.K. Clin. Chem. Lab. Med. (2006) [Pubmed]
  21. The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Kelemen, L.E. Int. J. Cancer (2006) [Pubmed]
  22. Expression and functional characterization of the beta-isoform of the folate receptor on CD34(+) cells. Reddy, J.A., Haneline, L.S., Srour, E.F., Antony, A.C., Clapp, D.W., Low, P.S. Blood (1999) [Pubmed]
  23. Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Nakashima-Matsushita, N., Homma, T., Yu, S., Matsuda, T., Sunahara, N., Nakamura, T., Tsukano, M., Ratnam, M., Matsuyama, T. Arthritis Rheum. (1999) [Pubmed]
  24. Transcellular transfer of folate across the retinal pigment epithelium. Bridges, C.C., El-Sherbeny, A., Ola, M.S., Ganapathy, V., Smith, S.B. Curr. Eye Res. (2002) [Pubmed]
  25. Interaction of folate receptor with signaling molecules lyn and G(alpha)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1. Miotti, S., Bagnoli, M., Tomassetti, A., Colnaghi, M.I., Canevari, S. J. Cell. Sci. (2000) [Pubmed]
  26. Clustering of GPI-anchored folate receptor independent of both cross-linking and association with caveolin. Wu, M., Fan, J., Gunning, W., Ratnam, M. J. Membr. Biol. (1997) [Pubmed]
  27. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Viel, A., Dall'Agnese, L., Simone, F., Canzonieri, V., Capozzi, E., Visentin, M.C., Valle, R., Boiocchi, M. Br. J. Cancer (1997) [Pubmed]
  28. Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting. Kelley, K.M., Rowan, B.G., Ratnam, M. Cancer Res. (2003) [Pubmed]
  29. Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. Evans, C.O., Young, A.N., Brown, M.R., Brat, D.J., Parks, J.S., Neish, A.S., Oyesiku, N.M. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  30. Membrane vesicles shed into the extracellular medium by human breast carcinoma cells carry tumor-associated surface antigens. Dolo, V., Adobati, E., Canevari, S., Picone, M.A., Vittorelli, M.L. Clin. Exp. Metastasis (1995) [Pubmed]
  31. Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. Paulos, C.M., Turk, M.J., Breur, G.J., Low, P.S. Adv. Drug Deliv. Rev. (2004) [Pubmed]
  32. Selective delivery of CB300638, a cyclopenta[g]quinazoline-based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor. Theti, D.S., Bavetsias, V., Skelton, L.A., Titley, J., Gibbs, D., Jansen, G., Jackman, A.L. Cancer Res. (2003) [Pubmed]
  33. Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates. Qi, H., Ratnam, M. Cancer Res. (2006) [Pubmed]
  34. Membrane receptors for endocytosis in the renal proximal tubule. Christensen, E.I., Birn, H., Verroust, P., Moestrup, S.K. Int. Rev. Cytol. (1998) [Pubmed]
  35. Tissue-specific promoters of the alpha human folate receptor gene yield transcripts with divergent 5' leader sequences and different translational efficiencies. Roberts, S.J., Chung, K.N., Nachmanoff, K., Elwood, P.C. Biochem. J. (1997) [Pubmed]
  36. Characterization of the formae speciales of Fusarium oxysporum causing wilts of cucurbits by DNA fingerprinting with nuclear repetitive DNA sequences. Namiki, F., Shiomi, T., Kayamura, T., Tsuge, T. Appl. Environ. Microbiol. (1994) [Pubmed]
  37. Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein. Coney, L.R., Tomassetti, A., Carayannopoulos, L., Frasca, V., Kamen, B.A., Colnaghi, M.I., Zurawski, V.R. Cancer Res. (1991) [Pubmed]
  38. The conversion of the human membrane-associated folate binding protein (folate receptor) to the soluble folate binding protein by a membrane-associated metalloprotease. Elwood, P.C., Deutsch, J.C., Kolhouse, J.F. J. Biol. Chem. (1991) [Pubmed]
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