Disease relevance of Folr2

• We previously identified two membrane-bound folate binding proteins, FBP1 and FBP2, in murine L1210 leukemia cells [1].
• Folic acid supplementation partially rescues wild type cells from arsenic toxicity, but Folbp2 null cells are not protected [2].
• METHODS: In the current study, we wanted to extend our findings and test the hypothesis that Folbp2(-/-) mice are more susceptible to the teratogenic effects of valproic acid (VPA), a commonly used antiepileptic drug that is known to induce neural tube defects (NTDs) in both humans and laboratory animals [3].
• The immunotoxin targeting FRbeta-expressing cells will provide a therapeutic tool for rheumatoid synovitis [4].
• FRbeta-expressing macrophages were produced by the transfection of adenovirus vector containing the FRbeta gene [4].

High impact information on Folr2

• Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10 [5].
• RESULTS: FRbeta-expressing cells were not present in peripheral blood leukocytes and their activated cells [4].
• The results of Northern analyses using probes specific to FBP2 5'-untranslated sequences or to a splice junction within this region suggest that the up-regulated FBP2-specific message in F2-MTXrA utilizes 5'-noncoding sequences distinct from those used in the message encoded in L1210 cell lines with low level FBP2 expression [6].
• The large increase in FBP2 expression in the F2-MTXrA line correlates with a 10-fold increase in [3H]folic acid membrane surface binding and a 1000-fold decrease in the folic acid growth requirement compared with parental L1210 cells [6].
• Substitution of the amino-terminal portion (residues 1-92) in the mature FR-alpha polypeptide with the corresponding segment of FR-beta resulted in folate binding characteristics similar to FR-beta [7].

Chemical compound and disease context of Folr2

• In order to better understand the role of folate transport mechanisms in arsenic-induced neural tube defects, we examined the effect of in utero exposure to sodium arsenate in a genetically altered murine model in which the folate binding protein 2 (Folbp2) gene has been inactivated by homologous recombination [8].

Biological context of Folr2

• The present study identifies the critical amino acid sequence divergence underlying functional differences between FR-alpha and FR-beta [7].
• Reciprocal substitution in FR-beta with peptide 1-92 of FR-alpha resulted in poor expression of a [3H]folic acid binding protein [7].
• 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 [9].
• Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice [10].
• Increased FR-beta expression in these cells can be induced by all-trans retinoic acid (ATRA) and other retinoid compounds in the absence of terminal differentiation or cell growth inhibition [11].

Anatomical context of Folr2

• 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 [12].
• Chimeric constructs of the cDNAs encoding human FR-alpha and FR-beta were expressed in human 293 fibroblasts [7].
• The expression of mRNA of FR-beta was dominant in bone marrow cells of CIA mice [13].
• Similar to FR-alpha (KB cells) and FR-beta (placenta), the protein was released from the membrane by phosphatidylinositol-specific phospholipase C, indicating a glycosylphosphatidylinositol (GPI) membrane anchor [14].

Associations of Folr2 with chemical compounds

• We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly [5].
• Based on the results of northern analysis and the mobilities of affinity-labeled proteins on polyacrylamide gels, these cell lines exhibit specific up-regulated expression of FBP1 or FBP2 [1].
• Because dietary folate is required to generate the methyl donor S-adenosyl methionine, we hypothesized that loss of folate binding protein 2 (Folbp2) results in increased susceptibility to arsenic-induced cytotoxicity [2].

Regulatory relationships of Folr2

• RESULTS: Folbp2(-/-) mice had higher VPA-induced frequencies of embryonic lethality and exencephaly than did the wild-type control mice during folate supplementation and a control diet, respectively [3].

References