Disease relevance of CSF1R

• The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia [1].
• This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromosome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q [1].
• Furthermore, the product of the proto-oncogene fms (c-fms) may be related or identical to the receptor for macrophage colony-stimulating factor (CSF-1). v-fms is the transforming gene of the McDonough strain of feline sarcoma virus (SM-FeSV) and belongs to the family of src-related oncogenes which have tyrosine-specific kinase activity [2].
• Expression of the macrophage colony-stimulating factor and c-fms genes in human acute myeloblastic leukemia cells [3].
• CSF-1R expression by JEG-3 and JAR choriocarcinoma cells was also investigated [4].

Psychiatry related information on CSF1R

• However, participation in physical activity (PA) benefits people with FMS [5].
• There was a significant difference between FMS patients and healthy controls on the measures of depression, difficulty in identifying feelings subscale of TAS (TAS-dif), and total alexithymia scores [6].
• RESULTS: FMS participants reported lower levels of positive affect (p < .01) and extraversion (p < .01) than OA participants [7].
• CONCLUSIONS: These findings suggest that self-efficacy may play a critical role in both the present and long-term PA of women with FMS [5].
• Chronic episodic disorders, such as depressive disorders, IBS, migraine, and FMS, have important commonalities, including cormorbidities, an absence of classic anatomic pathology in the tissues, a lack of objective findings on physical examination, and a lack of abnormal findings by routine laboratory and radiologic tests [8].

High impact information on CSF1R

• This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1 [9].
• DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus [10].
• The as yet unidentified c-fms promoter/enhancer sequences may be confined to the nucleotides separating the two genes or could potentially lie within the PDGF receptor gene itself [11].
• A 5' untranslated exon of the human CSF-1 receptor gene (c-fms) is separated by a 26 kb intron from the 32 kb receptor coding sequences [11].
• A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential [12].

Chemical compound and disease context of CSF1R

• Co-expression of M-CSF transcripts and protein, FMS (M-CSF receptor) transcripts and protein, and steroid receptor content in adenocarcinomas of the ovary [13].
• Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions [14].
• Increasing c-FMS (CSF-1 receptor) expression decreases retinoic acid concentration needed to cause cell differentiation and retinoblastoma protein hypophosphorylation [15].
• Post-transcriptional regulation of c-fms proto-oncogene expression by dexamethasone and of CSF-1 in human breast carcinomas in vitro [16].
• Bordetella pertussis fimbriae bind to sulfated sugars such as heparin through the major subunit Fim2 [17].

Biological context of CSF1R

• We have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R; 6 of 10 were hemizygous and 4 of 10 homozygous for CSF1R loss [1].
• We tested five tetranucleotide microsatellite markers (UT5085, L17686, D9S753, ACTBP2, and CSF1R) in the tumor specimens and paired surgical margins of the patients whose margins were negative on pathological examination [18].
• Thus, although both chimeric genes have similar effects in transactivation of the CSF1R promoter, they affect cell growth as tumor promoters differently in vivo [19].
• A 1-Mb YAC contig encompassing the CSF1R gene has been used to screen a fetal brain cDNA library, and this has resulted in the identification of two genes comprising one known gene previously localized to the region (ADRB2) and one known gene previously unlocalized [20].
• Sixty-two pedigrees from Finland gave a lod score of 1.36 at the CSF1R locus approximately 14 cM distal to IL9/D5S393, where positive results from three pedigree collections converged at the 1997 workshop [21].

Anatomical context of CSF1R

• The expression of two upregulated genes, HOXA4 and CSF1R, was significantly higher in patients with a white blood cell count higher than 30 x 10(9)/L cells [22].
• These results demonstrate that leukemic myeloblasts from a subset of patients with AML express transcripts for both the CSF-1 and CSF-1 receptor genes, often in the same leukemic cells in vitro [3].
• Expression vectors containing either normal or oncogenic point-mutated human c-fms genes were transfected into interleukin 3 (IL-3)-dependent 32D cells in order to determine the effects of CSF-1 signaling in this murine clonal myeloid progenitor cell line [23].
• Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages [24].
• NIH 3T3 cells cotransfected with the human c-fms proto-oncogene together with a 1.6-kilobase cDNA clone encoding a 256-amino-acid precursor of the human mononuclear phagocyte colony-stimulating factor CSF-1 (M-CSF) undergo transformation by an autocrine mechanism [25].

Associations of CSF1R with chemical compounds

• The human CSF1 receptor (CSF1R) is a 150-kDa transmembrane glycoprotein whose cytoplasmic tyrosine kinase domain is split by a kinase insert (KI) region of approximately 70 amino acids [26].
• The common region of loss in these three 5q- syndrome patients includes the macrophage colony-stimulating factor-1 receptor (CSF1R), secreted protein, acidic, cysteine-rich (SPARC), and glutamate receptor (GR1A1) genes [27].
• TGF-beta 1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS [28].
• Accelerated turnover of the human CSF-1 receptor was observed in response to CSF-1 and phorbol esters, but not after stimulation with IL-3 or bacterial lipopolysaccharide [29].
• FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance [30].

Physical interactions of CSF1R

• Deletion analysis of the c-fms promoter revealed that the region including a binding site for transcription factor PU.1 was required for transcriptional activity in human aortic medial smooth muscle cells [31].
• Induction of macrophage colony-stimulating factor receptor (c-fms) expression in vascular medial smooth muscle cells treated with heparin binding epidermal growth factor-like growth factor [32].

Enzymatic interactions of CSF1R

• FMS overexpression also progressively increased the relative amount of dephosphorylated RB protein induced, while reducing the total amount of RB protein [33].
• Although c-fms and several other proteins were shown to be phosphorylated in response to M-CSF, the functional consequences of this phosphorylation remain unclear [34].
• CSF-1-treated cells expressing the CSF1R/IRDelta960 are unable to phosphorylate IRS-1 and Shc (Chaika, O. V., Chaika, N., Volle, D. J., Wilden, P. A. , Pirrucello, S. J., and Lewis, R. E. (1997) J. Biol. Chem. 272, 11968-11974) [35].

Regulatory relationships of CSF1R

• IL-10 appears to induce macrophage development by up-regulating c-fms and, thereby, enhancing the sensitivity of the cells to endogenously produced M-CSF [36].
• KIT and FMS are also frequently expressed in AML and are closely related to FLT3 [37].
• IL-2 enhances c-fms expression in human monocytes [38].
• Similar to two other hematopoietic growth factor receptors, the c-fms (macrophage colony-stimulating factor receptor) and the c-kit genes, c-mpl has been discovered through the study of oncogenic retroviruses [39].
• PU.1 antisense oligonucleotides inhibited growth factor-induced c-fms expression and foam cell formation [31].

Other interactions of CSF1R

• The effects of CSF-1 are mediated through binding to specific, high-affinity surface receptors encoded by the c-fms gene [3].
• Epigenetic consequences of AML1-ETO action at the human c-FMS locus [40].
• The AML1-ETO complex does not disrupt binding of other transcription factors, indicating that c-FMS is not irreversibly epigenetically silenced [40].
• In contrast, whatever the concentration, G-CSF had no effect on c-fms mRNA or protein levels [41].
• We provide evidence that this multiprotein complex can interact with the tyrosine phosphorylated CSF-1 receptor through the unoccupied SH2 domain of Grb2 [42].

Analytical, diagnostic and therapeutic context of CSF1R

• The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides [1].
• CSF-1 and c-fms gene expression was investigated in fresh human acute myeloblastic leukemic cells by Northern blot hybridization using cDNA probes [3].
• Confocal microscopy revealed that the PY proteins are in close proximity to the CSF-1R at the plasma membrane [43].
• Southern blotting analysis of EcoRI-digested DNA showed that each of the PDGFR, c-fms, and FGFA alleles were deleted [44].
• As a further comparison of the actions of the two CSFs, CSF-1R and GM-CSFR levels were measured by flow cytometry, and it was shown that GM-CSFR levels decreased within 5 days of culture, independent of the conditions examined [45].

References