Disease relevance of FOLR2

• ATRA also increased FR-beta expression in vitro in myeloid leukemia cells from patient marrow [1].
• We have developed a model to investigate the biochemical and biological properties of this folate receptor by transfecting NIH/3T3 cells, which do not endogenously express FBP, with a vector containing the complementary DNA for the gp38 cloned from the ovarian carcinoma cell line IGROV1 [2].
• 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 [3].
• In conclusion, SNP rs651646 within the FRbeta gene is polymorphic but is not associated with neural tube defects within the Irish population [4].
• METHODS: An affinity-purified rabbit polyclonal antibody specific for FR-beta was employed for immunostaining representative bone marrow smears and peripheral blood smears from normal individuals and from a limited number of patients with various leukemias [5].

High impact information on FOLR2

• The repressor elements bound Fos family proteins; association of the proteins with the repressor elements correlated negatively with FR-beta expression in peripheral blood neutrophils and monocytes and also in KG-1 (AML) cells grown in the absence or in the presence of ATRA [6].
• The basal promoter activity of FR-beta resulted from synergistic interaction between Sp1 and ets binding sites (EBSs) and repression by upstream AP-1-like elements, whose action required EBSs [6].
• Furthermore, down-regulation of FR-beta in KG-1 cells treated with O-tetradecanoylphorbol 13-acetate (TPA) was accompanied by increased AP-1 binding to the repressor elements [6].
• 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 [7].
• Furthermore, there was apparent cross-talk between RARalpha and RARgamma selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-beta expression [1].

Chemical compound and disease context of FOLR2

• The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-beta expression in myeloid leukemia cells refractory to retinoid differentiation therapy [1].
• FR-beta expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition [1].
• Ovarian-carcinoma cell lines (OVCAR3, IGROVI, OVCA432, SW626 and SKOV3), grown in standard medium containing supra-physiological (2.3 microM) folate concentration, display different levels of reactivity with the anti-folate-binding-protein (FBP) monoclonal antibody MOv18, which recognizes the alpha-isoform of the protein [8].

Biological context of FOLR2

• The nucleotide sequences of two non-overlapping human genomic clones contain the FR-P3 gene, which spans 5148 bp, is composed of five exons, and is polymorphic relative to 5' restriction sites [9].
• The isolation of the FR-P3 gene will permit functional analysis of the cis and trans regulatory elements of the FR-P3 gene and the mechanisms involved in tissue-specific FR gene expression [9].
• Compared to the FR-P2 cDNA, the composite 1084 base-pair (bp) FR-P3 cDNA is homologous, but contains a unique 5' terminus and sequence differences within the open reading frame (ORF) and at the exon I-II junction [9].
• When the GPI-anchored folate receptor (FR) type beta was expressed transiently in human 293 fibroblasts, there was a roughly equal distribution of [3H]folic acid binding protein between the cell surface and the medium after 24 h over a wide range of expression levels of FR-beta [10].
• The results from this study indicate that a carboxyl-terminal peptide in FR-beta is efficiently proteolyzed intracellularly by a pathway that is independent of GPI signal recognition resulting in proper protein folding and secretion [10].

Anatomical context of FOLR2

• FR-beta, which is known to be present in the placenta, most likely arises from the maternal decidua normally associated with this tissue [11].
• 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 [11].
• These studies establish that it is the FR-alpha isoform, and not the FR-beta isoform, which is selectively expressed in the placental trophoblast cells [11].
• Compared with KB cells (a human cell line known for its elevated expression of FR-alpha), the abundance of FR-beta on CD34(+) cell surfaces was relatively low (approximately 8% of KB cell levels) [12].
• Immunoprecipitation studies using this antiserum indicated that the purified placental folate binding protein shared antigenic determinants with both the large Mr and small Mr folate binding proteins from human milk [13].

Associations of FOLR2 with chemical compounds

• Thus, blocks in the RARalpha-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-beta expression [1].
• FR-beta was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D(3), or transforming growth factor beta [1].
• The folate receptor, a glycosyl phosphatidylinositol anchored M(r) 38,000-39,000 glycoprotein, is coded for by at least two genes (FR alpha and FR beta) at 11q13 [14].
• FR-beta expression and folic acid binding capacity on the cell surface were examined by flow cytometric analysis and 3H-folic acid binding analysis [15].
• When deglycosylated with hydrogen fluoride, both FR-gamma and FR-beta delta showed similar apparent molecular weights on Western blots as predicted for the intact polypeptides.(ABSTRACT TRUNCATED AT 250 WORDS)[16]
• Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue [17].

Regulatory relationships of FOLR2

• Among acute nonlymphocytic leukemias, FR-beta was expressed in promyelocytic leukemia, in the myeloblast populations of myelomonocytic and erythroleukemias, and variably in M1/M2 AML [5].
• RESULTS: RT-PCR, Northern blot, and Western blot analyses showed that FR-beta mRNA and protein were expressed selectively in activated monocytes and CD14+ RA SMC [15].

Other interactions of FOLR2

• The less differentiated FR-beta positive AML samples also were positive for CD34 and HLA-DR [5].
• Furthermore, the mRNA level for FR-gamma did not exceed that for FR-beta delta [16].
• Using polymerase chain reaction methodology, Northern blot analysis, immunoblotting, and immunofluorescence, we find relatively limited expression of FR alpha and no FR beta in UMSCC38 cells when compared to nonamplified lines [14].
• The findings suggest that folate antagonists with higher affinity for FR-beta would be useful in the treatment of RA [15].
• Similar recombinant CHO cell lines were produced that expressed the glycosylphosphatidylinositol-(GPI-) anchored FR type beta and a truncated form of FR type beta (FR-beta delta), in which the normal carboxyl-terminal signal for GPI anchor attachment was deleted [16].

Analytical, diagnostic and therapeutic context of FOLR2

• The transcript size (1084 bp) predicted from structural analysis of the FR-P3 gene correlates with the size (1100 bp) determined by Northern blots [9].
• Expression of FR-beta mRNA and protein was determined by Northern blot and Western blot analyses in RA SMC and monocyte/macrophage-lineage cells [15].
• Antiserum was raised in a rabbit, and on immunodiffusion, gave a single precipitin line with the purified placental folate binding protein [13].
• Multiple samples of normal bone marrow and peripheral blood were analyzed for the expression of FR-beta and selected CD antigens by two- or three-color flow cytometry [5].
• In this report, we describe the development of a quartz crystal microbalance biosensor for detection of folate binding protein (FBP) [18].

References