Disease relevance of Folr1

• 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].
• 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].
• 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].
• Distinguishing between folate receptor-alpha-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells [3].
• The expression of a membrane-associated folate receptor (FR) was elevated in spleen samples from patients with chronic (CML) and acute (AML) myelogenous leukemias compared with normal spleen [4].

Psychiatry related information on Folr1

• We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1(-/-) embryos [5].

High impact information on Folr1

• Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10 [6].
• To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice [6].
• Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development [6].
• Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups [6].
• Transduction of folate receptor cDNA into cervical carcinoma cells using recombinant adeno-associated virions delays cell proliferation in vitro and in vivo [7].

Chemical compound and disease context of Folr1

• Comparison of methotrexate polyglutamylation in L1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor. Lack of evidence for influx route-specific effects [8].
• Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects [5].
• Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid [9].
• Role of membrane folate-binding protein in the cytotoxicity of 5,10-dideazatetrahydrofolic acid in human ovarian carcinoma cell lines in vitro [10].
• In this study, FR-targeted liposomal daunorubicin was evaluated in an FR+ L1210JF murine ascites tumor model for therapeutic efficacy in vivo [11].

Biological context of Folr1

• Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation [1].
• Furthermore, additional amino acid sequence divergence at one or more positions downstream of residue 92 in FR-alpha is also an essential determinant of the unique functional characteristics of this receptor isoform [12].
• Reciprocal substitution in FR-beta with peptide 1-92 of FR-alpha resulted in poor expression of a [3H]folic acid binding protein [12].
• As the chromosomal locations of Folbp1 murine and Folbp2 genes were previously unknown, we utilized the same approach and mapped both genes to a region of mouse chromosome 7 that is syntenic to the human FR loci on chromosome 11q13 [13].
• We now report on the transfection of MTXrA with a cDNA encoding the murine homolog of the human folate receptor isoform of KB cells to produce MTXrA-TF1, which constitutively expresses high levels of FR-alpha [3].

Anatomical context of Folr1

• Compared to parental L1210 cells, expression of the FBP2-encoding transcript was unchanged in this cell line and, while the exact nature of the protein is unclear, FBP2 may represent a fetal form of the FBP [14].
• Folbp1 is heavily expressed in choroid plexus, yolk sac, and placenta, supporting a role of folbp1 in folate transport in other tissues [15].
• Chimeric constructs of the cDNAs encoding human FR-alpha and FR-beta were expressed in human 293 fibroblasts [12].
• Levels of folate-binding protein alpha were also increased in both small intestine and kidney in folate-deficient mice (91- and 2-fold, respectively) [16].
• Expression of folate receptor alpha in the mammalian retinol pigmented epithelium and retina [17].

Associations of Folr1 with chemical compounds

• Using an oligonucleotide probe complementary to the human FBP, we have cloned and sequenced two murine FBP cDNAs isolated from a library constructed using a L1210 subline adapted for growth on low levels of 5-formyltetrahydrofolate [14].
• The highly sensitive SWV strain demonstrated a significant reduction in the expression of the folate binding protein (FBP-1) following the teratogenic insult at gestational day 8:18, while the more resistant LM/Bc embryos were up-regulating this gene in response to valproic acid treatment [18].
• The MTXrA cells provide an example of a line selected for primary resistance to methotrexate that also exhibits concomitant increased expression of a folate-binding protein [19].
• 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].
• Probenecid and sulfobromophthalein inhibit methotrexate influx in both L1210 and MTXrA-TF1 cell lines; however, inhibition in MTXrA-TF1 could be accounted for on the basis of inhibition of methotrexate binding to FR-alpha [3].

Other interactions of Folr1

• Massive apoptosis was detected in the Folbp1-/- defective tissues, with Bax and activated caspase-3 distributed evenly across the apico-basal axis of the lateral neural plate [20].
• Insertion of an intracisternal A particle within the 5'-regulatory region of a gene encoding folate-binding protein in L1210 leukemia cells in response to low folate selection. Association with increased protein expression [21].
• Pre-optimization studies revealed that inclusion of low amounts (0.01 to 0.03%) of FA-Cys-PEG-PE yielded the highest binding activity of dioleoylphosphatidylcholine/cholesterol liposomes to folate receptor-bearing cells [22].

Analytical, diagnostic and therapeutic context of Folr1

• Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs) [23].
• Sequence analysis indicates that, with exception of the 5'-region, the FBP1-encoding locus in both cell lines is identical [21].
• RESULTS: RT-PCR analysis, cloning of the RT-PCR product, and subsequent sequencing established that folate receptor alpha mRNA transcripts are expressed in the mouse RPE/choroid and are expressed also in the neural retina [17].
• In situ hybridization localized the folate receptor alpha mRNA to the mouse RPE cells and to cells of the neural retina [17].
• Laser scanning confocal microscopy revealed the distribution of the folate receptor alpha along the basolateral region of the RPE and not the apical region [17].

References