Oncogenic potential of the c-FMS proto-oncogene (CSF-1 receptor).
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Animals↗
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Results for “Genes, fms”
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The reversal of the metastatic phenotype by gene transfer.
When studying the function of MHC-restricted immune responses in controlling metastatic growth we discovered that highly metastatic clones of mouse tumours express the H-2D but lack expression of the H-2K gene of the MHC system. The de novo expression of the H-2K antigen, after H-2K gene transfection, resulted in the reversal of a metastatic to a non-metastatic phenotype. This reversal was causally related to the acquisition of H-2K-restricted immunogenic properties. Immunization with H-2K-transfected cells, after surgical removal of the local tumour, abolished or significantly reduced the growth of metastases. We subsequently observed that H-2K expression is correlated with expression of the c-fos oncogenes. Transfection of H-2K-negative cells with v-fos or c-fos genes resulted in the expression of H-2K. Our studies suggest that one of the main functions of the c-fos proto-oncogenes is control of the expression of the MHC genes. Searching for additional molecular properties which characterize the metastatic phenotype, we observed that the metastatic clones of each of our lung-metastasizing tumours expresses an fms-related oncogene. This was correlated with a membrane-bound tyrosine kinase, which has the properties of growth factor receptors. We examine the possibility that our fms-like gene codes for this protein kinase, which represents a receptor for a local growth factor that controls metastatic growth in the lung.
Animals↗
Activation of the feline c-fms proto-oncogene: multiple alterations are required to generate a fully transformed phenotype.
The v-fms oncogene is capable of producing tumors in vivo and transforming cells in culture; in contrast, the c-fms proto-oncogene is nontransforming. In this report we present the complete nucleotide sequence of a feline c-fms cDNA, the progenitor of the v-fms oncogene. Comparison of this sequence with that of v-fms shows that the proteins encoded by these two genes differ by nine amino acid substitutions and the replacement of 50 C-terminal amino acids present in c-fms by 11 unrelated residues in v-fms. Using chimeric fms genes and site-directed mutagenesis, we have determined that the C-terminal modification present in v-fms is sufficient to generate a partially transforming phenotype, but that mutations at amino acid positions 301 and 374 are required (in addition to the C-terminal modification) to generate a fully transforming fms gene.
Amino Acid Sequence↗
Transcription of c-onc genes c-rasKi and c-fms during mouse development.
We investigated the expression of cellular sequences c-rasKi and c-fms, which are homologous to the oncogenes of Kirsten rat sarcoma virus and the McDonough strain of feline sarcoma virus, during murine development and in a variety of mouse tissues. The c-rasKi gene was found to be transcribed into two mRNA species of approximately 2.0 and 4.4 kilobases, whereas a single c-fms-related transcript of approximately 3.7 kilobases was identified. The c-rasKi gene appeared to be expressed ubiquitously, since similar levels of transcripts were observed in embryos, fetuses, extraembryonal structures, and a variety of postnatal tissues. In contrast, significant expression of c-fms was found to be confined to the placenta and extraembryonal membranes (i.e., combined yolk sac and amnion). The concentration of c-fms transcripts in the placenta increased approximately 15-fold (relative to day-7 to day-9 conceptuses) during development before reaching a plateau at day 14 to 15 of gestation. The time course of cfms expression in the extraembryonal membranes appeared to parallel the stage-specific pattern observed in the placenta. The level of c-fms transcripts in the extraembryonal tissues reached a level which was approximately 20- to 50-fold greater than that in the fetus. These findings suggest that the c-fms gene product may play a role in differentiation of extraembryonal structures or in transport processes occurring in these tissues. Our results indicate that the c-onc genes analyzed in the present study exert essentially different functions during mouse development.
Animals↗
Dinucleotide repeat polymorphism at the human c-fms protooncogene for the CFS-1 receptor (CFS1R).
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Base Sequence↗
Induction of the fms proto-oncogene product in HL-60 cells by vitamin D: a flow cytometric analysis.
Agents which induce monocytic characteristics in HL-60 human acute promyelocytic leukemia cells induce mRNA for the fms proto-oncogene, which encodes the receptor for M-CSF. Previous studies of fms expression in HL-60 cells have characterized chiefly induction by phorbol esters of fms mRNA. Our studies of fms expression in HI-60 cells have characterized induction by vitamin D3 of the fms protein. We have used flow cytometry to correlate fms antigen with a monocyte-specific differentiation antigen recognized by antibody MO2 (CD14), with DNA content, and with the nuclear antigen Ki-67, a marker of cell cycling. HL-60 cells were cultured with or without 1 microM vitamin D for 7 days. fms antigen was found on 42 +/- 5.8% of the cells cultured without vitamin D, but on 63 +/- 4.3% of the cells cultured with vitamin D. MO2 binding was detected on only 2 +/- 0.5% of the cells without vitamin D, but on 59 +/- 9% with vitamin D. Cells cultured with vitamin D that were fms-positive were also predominantly (83%) MO2-positive. Analysis of DNA content, measured by propidium iodide staining, showed that 57 +/- 1.5% of cells cultured without vitamin D, but 93 +/- 0.5% of cells cultured with vitamin D, were in the G0/G1 cell cycle phase. Analysis of nuclear antigen Ki-67 revealed that, of the vitamin D-treated cells that were fms-positive, a significant proportion (37%) were still cycling. We conclude that (1) fms is demonstrable on some uninduced HL-60 cells, (2) when HL-60 cells are induced to develop monocytic characteristics by vitamin D, fms induction is part of the program for monocytic differentiation that includes MO2 expression, yet (3) some induced cells expressing fms are still cycling.
Antigens, Differentiation↗
c-FMS mutational analysis in acute myeloid leukaemia.
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Acute Disease↗
The proto-oncogene c-fms is overexpressed in endometrial cancer.
Recent studies have shown that macrophage colony-stimulating factor and its receptor c-fms protein are significantly overexpressed in endometrial and ovarian cancers. In the present study, we analyzed the steady-state levels of c-fms mRNA in benign and malignant endometrial tissues by Northern and slot blot analyses. The relative levels of c-fms mRNA were quantified by using a hybridization signal for each sample on Northern blot analysis. Slot blot analysis was used to further quantitate the relative increase in c-fms mRNA in malignant specimens compared to benign specimens. Correlation of c-fms expression in the endometrial cancers was made with traditional prognostic indicators. Secretory endometrium had low levels of c-fms mRNA, whereas the endometrial cancers had the highest levels. Proliferative and hyperplastic endometrium values were intermediate. Comparative assessment of c-fms expression in endometrial cancer relative to other prognostic factors demonstrated greater expression of c-fms in specimens from patients with abnormal DNA ploidy, high-grade lesions, and possibly extrauterine metastases. Our study confirms the overexpression of c-fms in endometrial cancer and demonstrates a positive correlation between the steady-state mRNA levels of c-fms and other select adverse prognostic indicators.
Endometrial Neoplasms↗
Increased methylation of the c-fms protooncogene in acute myelomonocytic leukemias.
DNA methylation provides an epigenetic information possibly involved in differentiation processes and gene regulation. In this study we investigated the methylation state of the c-fms/M-CSF receptor gene in normal human blood cells and leukemias. The methylation pattern of the c-fms gene as detected by isoschizomeric restriction analysis with MspI/HpaII showed only slight interindividual variations in normal donors, but there were constant differences between granulocytes and monocytes from the same donor. Of 21 acute myelomonocytic leukemias investigated, 85% revealed a methylation pattern different from that of normal monocytes. One or more restriction sites which were at least partly unmethylated in normal monocytes proved to be methylated in leukemic cells. In contrast, leukemias of lymphocytic origin showed hypomethylation of the c-fms gene. There was no correlation between the methylation state of the c-fms gene and its expression at the RNA level, but an increase in monocyte/macrophage-specific differentiation markers could be observed in those samples which exhibited a methylation pattern similar to that of normal monocytes. The increased DNA methylation within the c-fms gene might reflect the inactivation of differentiation genes in leukemic cell clones, contributing to their maturation arrest. Furthermore, neoplastic hematopoietic cells seem to exhibit lineage-specific differences in c-fms gene methylation.
Adolescent↗
Isolation and characterization of new mammalian kinase genes by cross hybridization with a tyrosine kinase probe.
We isolated two novel mammalian kinase genes by weak cross-hybridization with v-ros oncogene. (1) A cDNA of about 7.7 kb obtained from a human placenta cDNA library carried a 4.2 kb open reading frame, and the predicted amino acid sequence of 1338 residues contained extracellular, transmembrane and tyrosine kinase domains. The overall structure including cysteine motifs in its extracellular domain and a long peptide insertion in its tyrosine kinase domain indicates that this new gene is closely related to the fms family. Consequently, the gene was designated as flt(fms-like tyrosine kinase) gene. The expression of the flt gene was examined in normal and transformed cells, and it was mapped to human chromosome 13q12-13. (2) Another new gene was found to be expressed almost exclusively in testis. The cDNA sequence analysis revealed that the predicted product carried protein kinase consensus motifs in its amino-terminal region. Comparison of the deduced amino acid sequence of this gene in the kinase domain with those of other protein kinase genes will be discussed.
Amino Acid Sequence↗
An unexpected effect of glucocorticoids on stimulation of c-fms proto-oncogene expression in choriocarcinoma cells that express little glucocorticoid receptor.
OBJECTIVE: The purpose of this study was to determine the mechanism by which glucocorticoids stimulate c-fms proto-oncogene expression in JAR choriocarcinoma cells, which are reported to lack the glucocorticoid receptor. STUDY DESIGN: Glucocorticoid action on c-fms was tested with the use of ligand binding assays, Northern and Western blotting, immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction, and nuclear run-off experiments. RESULTS: Dexamethasone stimulated c-fms (EC(50)=1 nmol/L) in JAR cells in a specific manner. Both RU 486 and actinomycin D inhibited dexamethasone stimulation, which suggests receptor-mediated and transcriptionally regulated actions. Neither cytosol or whole cell binding assays nor immunohistochemistry detected glucocorticoid receptor in JAR cells. However, Southern blot analysis of reverse transcriptase-polymerase chain reaction products revealed levels of glucocorticoid receptor messenger RNA in JAR cells that were approximately 100-fold lower than in HeLa control cells. In all but 1 clone among several JAR clones that were tested, there was concordance between presence or absence of glucocorticoid receptor messenger RNA and glucocorticoid sensitivity. CONCLUSION: Some JAR cells contain low levels of glucocorticoid receptor, which mediate dexamethasone stimulation of c-fms expression. Such sensitivity to circulating glucocorticoids confers a survival advantage to these cells by stimulating the c-fms-related invasive behavior so characteristic of choriocarcinomas.
Blotting, Northern↗
[Methylation status of c-fms oncogene in hepatocellular carcinoma and its relation with clinical pathology].
OBJECTIVE: To study the methylation status change of c-fms oncogene in hepatocellular carcinogenesis, and to clarify the abnormal highly expressing mechanism of c-fms/CSF-1R in hepatocellular carcinoma (HCC). METHODS: Genome DNA of 30 cases of HCC tissue and matching surrounding-cancer tissue were digested with restrictive endonucleases Hpa II/Msp I. Methylation status of c-fms oncogene was tested with Southern blot. Methylation status of c-fms oncogene in the HCC tissue and the matching surrounding-cancer tissue was compared. The relation between methylation status of c-fms oncogene and clinical pathology of HCC was determined. RESULTS: Methylation status of c-fms oncogene decreased in 36.7% (11/30) HCC tissue and 13.3% (4/30) matching surrounding-cancer tissue. The hypomethylation rate of c-fms oncogene in the HCC tissue was higher than that in the matching surrounding-cancer tissue. There was significant correlation between Edmondson scale of HCC and hypomethylation of c-fms oncogene. The hypomethylation rate of HCC in Edmondson III-IV was higher than that in Edmondson I-II. CONCLUSIONS: Hypomethylation of c-fms oncogene may be an important molecular mechanism leading to abnormally high expressing of CSF-1R, which contributes to occurrence and deterioration of HCC.
Adult↗
Comparison of gene expression in bovine aortic endothelium in vivo versus in vitro. Differences in growth regulatory molecules.
Many studies of the endothelium have assumed equivalence between cultured confluent cells and an endothelial lining in vivo. We compared gene expression of bovine aortic endothelial cells (BAECs) in culture versus freshly isolated cells from bovine aortas. Our technique of harvesting in vivo tissue yielded cells that were endothelial by the criteria of their containing von Willebrand factor (vWF) and lacking smooth muscle alpha-actin, by both immunocytochemistry and mRNA analyses. We found that several genes are overexpressed when BAECs are placed into culture, including basic fibroblast growth factor, platelet-derived growth factor B-chain, and thrombospondin. On the other hand, message for vWF is highly expressed in vivo and at lower levels in confluent cultures. The transcripts for transforming growth factor-beta, plakoglobin, and flg (fms-like gene, FGF receptor-1) are comparable in vitro and in vivo. These results demonstrate that significant changes in gene expression occur in the transition from in vivo conditions to tissue culture of endothelial cells. Studies of in vitro endothelium may poorly reflect a quiescent endothelial lining in vivo but may be more similar to cells responding to injury or angiogenic stimuli.
Actins↗
Detection of c-fms protooncogene in early mouse embryos by whole mount in situ hybridization indicates roles for macrophages in tissue remodelling.
The c-fms protoncogene which encodes the receptor for macrophage colony-stimulating factor (CSF-1) was localized in the developing mouse embryo by whole in situ hybridization. c-fms was expressed first in placental trophoblasts. Around 9.5 dpc, isolated c-fms-positive cells became detectable in the yolk sac and by 10.5 dpc large numbers were detectable throughout the embryo. The localization of c-fms expression was consistent with its restriction to macrophages, and with the location of those macrophages in sites of tissue turnover and extensive cell death.
Animals↗
Modulation of c-fms proto-oncogene in an ovarian carcinoma cell line by a hammerhead ribozyme.
Co-expression of macrophage colony-stimulating factor (M-CSF) and its receptor (c-fms) is often found in ovarian epithelial carcinoma, suggesting the existence of autocrine regulation of cell growth by M-CSF. To block this autocrine loop, we have developed hammerhead ribozymes against c-fms mRNA. As target sites of the ribozyme, we chose the GUC sequence in codon 18 and codon 27 of c-fms mRNA. Two kinds of ribozymes were able to cleave an artificial c-fms RNA substrate in a cell-free system, although the ribozyme against codon 18 was much more efficient than that against codon 27. We next constructed an expression vector carrying a ribozyme sequence that targeted the GUC sequence in codon 18 of c-fms mRNA. It was introduced into TYK-nu cells that expressed M-CSF and its receptor. Its transfectant showed a reduced growth potential. The expression levels of c-fms protein and mRNA in the transfectant were clearly decreased with the expression of ribozyme RNA compared with that of an untransfected control or a transfectant with the vector without the ribozyme sequence. These results suggest that the ribozyme against GUC in codon 18 of c-fms mRNA is a promising tool for blocking the autocrine loop of M-CSF in ovarian epithelial carcinoma.
Base Sequence↗
c-fms is present in primary tumours as well as in their metastases in bone marrow.
The expression of c-fms oncoprotein in different primary tumours as well as in their metastases in bone marrow, was shown. All the samples were fixed and processed by the acetone, methyl benzoate, xylene procedure (AMeX), which was suitable for studying oncoprotein expression not only in primary tumours but also in bone marrow (BM) biopsies. Among the patients suffering from acute myeloid leukaemia (AMeL), positive c-fms cells were found in 55% cases. On the contrary, patients with lymphocytic cell disorders have not had detectable c-fms oncogene product in BM biopsies.c-fms oncoprotein was also detected in some primary tumour specimens (lung carcinoma, cervical carcinoma, gastric carcinoma, breast carcinoma and melanoma) and their metastases in BM, while it was not present in normal uterine tissue. There was a positive correlation between c-fms oncoprotein expression in primary and metastatic tumours. Our results showed that c-fms product is confined, not only to some normal, but also to the variety of malignant cells of different origin.
Acetone↗
Colony-stimulating factor-1 impairs both proliferation and differentiation signals of erythropoietin during the commitment of bipotential NFS-60 cell line to the monocytic lineage.
The interleukin-3 (IL-3) dependent cell line NFS-60 contains bipotential progenitors that exhibit both erythroid and myelomonocytic potentials. In order to study their commitment to the monocytic lineage, NFS-60 cells were retrovirally transduced with mouse c-fms cDNA, which encodes the colony-stimulating factor-1 receptor (CSF-1R), resulting in the N-Fms cell line. N-Fms cells proliferated in response to CSF-1 with a growth rate similar to that obtained in response to IL-3 and progressively differentiated from myeloid blasts to monocytic cells within 3 days of culture. When maintained in IL-3, about 3% of N-Fms cells formed large hemoglobinized colonies in semisolid cultures supplemented with erythropoietin (EPO). However, this property was lost after a 24-hour cultivation in the presence of CSF-1 or, interestingly, both CSF-1 and IL-3. This loss of response to EPO was reverted following a brief passage (24 hours) in IL-3, but the rescued colonies did not undergo terminal erythrocytic differentiation. Furthermore, CSF-1 also affected proliferative response to EPO of N-Fms cells constitutively expressing EPO receptors. Our data strongly suggest that CSF-1 can suppress erythroid potential in bipotential N-Fms cells by altering proliferative and differentiation signal of EPO.
Animals↗
Identification of differentially expressed genes between osteoarthritic and normal trabecular bone from the intertrochanteric region of the proximal femur using cDNA microarray analysis.
Osteoarthritis (OA) is a common age-related joint disease resulting in progressive degenerative damage to articular cartilage. The etiology of primary OA has not yet been determined. However, there is evidence supporting the hypothesis that primary OA is a disease affecting bone remodeling in addition to articular cartilage. In this study, we have used cDNA microarray analysis to compare gene expression in bone between normal (CTL) and OA individuals. Trabecular bone was sampled from the intertrochanteric region of the proximal femur, a site distal to the diseased hip joint. Total RNA was extracted from three pairs of age- and sex-matched CTL and OA bone samples, reverse-transcribed and radioactively labeled to generate cDNA probes, before hybridization with the Research Genetics GF211 human gene microarray filter. The CTL and OA samples were found to have similar levels of gene expression for more than 4000 known human genes. However, forty-one genes were identified that were differentially expressed, twofold or more, between all three CTL-OA sample pairs. Using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, three genes, fms-like tyrosine kinase 1 (FLT1), plexin B1 (PLXNB1), and small inducible cytokine A2 (SCYA2), were confirmed to be consistently expressed at lower levels in OA, in a majority of twenty age- and sex-matched CTL-OA bone sample pairs tested. FLT1, PLXNB1, and SCYA2 have known or potential roles in angiogenesis and bone remodeling. Down-regulation of these genes is consistent with a role for bone in the pathogenesis of OA.
Aged↗