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PubMed2001

Genetic factors in ovarian carcinoma.

Recent evidence indicates that inherited and acquired genetic mutations are the driving force behind carcinogenesis and cellular transformation. This review examines a number of proto-oncogenes and tumor suppressor genes that are associated with ovarian carcinomas, including p53, BRCA1, and BRCA2; mismatch repair genes such as hMSH2 and hMLH1; and PTEN, HER-2/neu, K-ras, fms, and AKT2. Novel genes recently implicated in ovarian tumorigenesis are discussed, including NOEY2, OVCA1, and PIK3CA. Although no singular gene alteration has been shown to initiate transformation in the ovarian epithelium, elucidation of the complex molecular and cellular mechanisms involving these known gene mutations may result in new clinical management strategies.

BRCA1 Protein↗
PubMed1999

Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique.

To screen the receptor genes in renal cell carcinoma (RCC) associated with angiogenesis, we performed differential hybridization of the cDNA library of membrane-type protein tyrosine kinases (mPTKs). Three thousand plaques of a mPTKs-enriched cDNA library were screened with mPTKs mixture probes produced from hypervascular RCC tissues and RCC cell lines. Six different cDNA fragments of the PTK genes were isolated, and the sequence analysis showed that these represented cDNAs for TIE1, KDR, FMS, FGFR-4, JAK1 and HCK. Of these genes, the expression of TIE1, KDR, and FGFR-4 was studied in RCC tissue and cell lines by Northern blot analysis. We also investigated the expression of vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptor FLT-1. In all the hypervascular RCC tissues, the amounts of mRNAs for KDR and FLT-1 were increased compared to adjacent normal tissues. The TIE1 and FGFR-4 genes were also overexpressed in most of the hypervascular RCC tissues, while no mRNA of KDR, FLT-1, or TIE1 could be detected in any of the four human RCC cell lines. The amounts of the VEGF and PlGF mRNAs were increased in hypervascular RCC tissues, while VEGF mRNA was detected in the four cell lines but PlGF mRNA was not. FGFR-4 mRNA was expressed in three of the four cell lines. These results suggest that KDR, FLT-1, PlGF and TIE1 mRNAs are present in the mesenchymal cells of RCC, while VEGF and FGFR-4 genes are expressed in RCC cells themselves in vivo.

Blotting, Northern↗
PubMed2002

Transcription factor complex formation and chromatin fine structure alterations at the murine c-fms (CSF-1 receptor) locus during maturation of myeloid precursor cells.

Expression of the gene for the macrophage colony stimulating factor receptor (CSF-1R), c-fms, has been viewed as a hallmark of the commitment of multipotent precursor cells to macrophages. Lineage-restricted expression of the gene is controlled by conserved elements in the proximal promoter and within the first intron. To investigate the developmental regulation of c-fms at the level of chromatin structure, we developed an in vitro system to examine the maturation of multipotent myeloid precursor cells into mature macrophages. The dynamics of chromatin fine structure alterations and transcription factor occupancy at the c-fms promoter and intronic enhancer was examined by in vivo DMS and UV-footprinting. We show that the c-fms gene is already transcribed at low levels in early myeloid precursors on which no CSF-1R surface expression can be detected. At this stage of myelopoiesis, the formation of transcription factor complexes on the promoter was complete. By contrast, occupancy of the enhancer was acutely regulated during macrophage differentiation. Our data show that cell-intrinsic differentiation decisions at the c-fms locus precede the appearance of c-fms on the cell surface. They also suggest that complex lineage-specific enhancers such as the c-fms intronic enhancer regulate local chromatin structure through the coordinated assembly and disassembly of distinct transcription factor complexes.

Animals↗
PubMed1990

c-fms expression in acute leukemias with complex phenotypes.

The c-fms proto-oncogene product, which is the receptor for the macrophage colony-stimulating factor CSF-1, is always found expressed in acute myeloid leukemia cells, irrespective of their stage of differentiation according to the FAB classification (Dubreuil P, Torrès H, Courcoul M, Birg F, Mannoni P. Blood 1988;72:1081-1085). We have extended this study and looked for c-fms expression in poorly differentiated myeloid leukemias, in a series of acute leukemias of either T or B origin and in biphenotypic leukemias. We now report that expression of c-fms is still related to the myeloid origin of the leukemic proliferation, but that it can also be found in some acute leukemias presenting clonal rearrangements of the T cell receptor gene. Thus expression of the c-fms/CSF-1 receptor may not be exclusively a marker for myeloid proliferations.

Acute Disease↗
PubMed1991

Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion.

A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, comprising the interleukins 3, 4, and 5, macrophage colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, and the receptor for macrophage-colony-stimulating factor [the CSF1R (formerly FMS) gene product], have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R, which is required for normal proliferation and differentiation of hemopoietic cells of the myeloid lineage. We have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromosome 5, in 10 patients with myelodysplasia and a 5q deletion. 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. 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. In those patients considered to have homozygous CSF1R loss by DNA experiments the gene was deleted from the 5q chromosome in all cells and from the apparently normal chromosome 5 in a subset of cells. 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. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.

Adult↗
PubMed1987

Expression of a fms-related oncogene in carcinogen-induced neoplastic epithelial cells.

Following carcinogen exposure in vitro, normal rat tracheal epithelial cells are transformed in a multistage process in which the cultured cells become immortal and, ultimately, neoplastic. Five cell lines derived from tumors produced by neoplastically transformed rat tracheal epithelial cells were examined for the expression of 11 cellular oncogenes previously implicated in pulmonary or epithelial carcinogenesis. RNA homologous to fms was expressed at a level 5-19 times higher than normal tracheal epithelial cells in three of five of the tumor-derived lines. All three lines expressing high levels of fms-related RNA gave rise to invasive tumors of epithelial origin when injected into nude mice. Increased expression of the fms-related mRNA was not due to gene amplification, and no gene rearrangement was detected by Southern analyses. RNA blot analysis using a 3' v-fms probe detected a 9.5-kilobase message in the three tumor-derived lines, whereas both normal rat alveolar macrophages and the human choriocarcinoma line BeWo expressed a fms transcript of approximately 4 kilobases. We conclude from these data that the gene expressed as a 9.5-kilobase transcript in these neoplastic epithelial cells is a member of a fms-related gene family but may be distinct from the gene that encodes the macrophage colony-stimulating factor (CSF-1) receptor.

Animals↗
PubMed1988

Modulation of c-fms proto-oncogene expression in human blood monocytes and macrophages.

The gene product of the c-fms proto-oncogene is a transmembrane protein with tyrosine-kinase activity that is obviously related to the receptor for the colony-stimulating-factor CSF-1. By Northern blot analysis, we investigated the expression of the cellular counterpart of v-fms in purified normal human blood mononuclear cells and different macrophage populations. The proto-oncogene c-fms expression was demonstrable in blood monocytes but not in blood lymphocytes. Short-term cultivated blood monocytes exhibited an increased expression of c-fms in comparison to freshly isolated blood monocytes, possibly due to a temporary down regulation of c-fms during the separation procedure of blood monocytes. A comparably high rate of fms-RNA expression was found in most of the analyzed samples of resident peritoneal macrophages, while resident alveolar macrophages showed a considerably lower level of c-fms expression. In this, alveolar macrophages resembled long-term cultivated adherent blood monocytes, which showed a down regulation of c-fms expression. By correlating these data obtained by Northern blot analysis with phenotypic properties of the analyzed monocyte/macrophage populations, it is concluded that different levels of c-fms expression in monocytes/macrophages correspond to their stage of differentiation and maturity.

Cell Differentiation↗
PubMed1990

CD14 is a member of the family of leucine-rich proteins and is encoded by a gene syntenic with multiple receptor genes.

We have isolated and characterized genomic and cDNA clones encoding the murine homolog of the human monocyte/granulocyte cell surface glycoprotein, CD14. As in man, the expression of murine CD14 is limited to the myeloid lineage. The murine and human CD14 genes are highly conserved in their intron-exon organization and nucleotide sequence. Their deduced protein sequences show 66% amino acid identity. In both mouse and man, the CD14 protein contains a repeating (10 times) leucine-rich motif (LXXLXLX) that is also found in a group of heterogeneous proteins from phylogenetically distant species. The CD14 gene has been mapped to mouse chromosome 18 which also contains at least five genes encoding receptors (Pdgfr, Adrb2r, li, Grl-1, Fms). Thus CD14 and the receptor genes form a conserved syntenic group localized on mouse chromosome 18 and human chromosome 5. The inclusion of CD14 in the family of leucine-rich proteins, its expression profile and the murine chromosomal localization support the hypothesis that CD14 may function as a receptor.

Amino Acid Sequence↗
PubMed2006

Circulating angiogenic proteins in trisomy 13.

OBJECTIVE: Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. STUDY DESIGN: Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. RESULTS: In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. CONCLUSION: These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

Angiogenic Proteins↗
PubMed1989

Dissociation of cellular proliferation and c-myc expression by buttercup extract.

Buttercup extract (BE), an extract of the buttercup plant (Zanthoriza simplicissima), inhibits RNA and DNA synthesis by HL-60 promyelocytic leukemia cells. Exposure of these cells to 3% BE for 48 hours results in dramatic inhibition of RNA synthesis without loss of cell viability. The effect of BE is partially reversible over 12-24 hours with the level of RNA synthesis returning nearly to control levels during this time period. DNA synthesis is also reversibly inhibited by exposure to BE. Despite the inhibition of RNA synthesis in HL-60 cells, there is no decrease in the level of c-myc mRNA, even at high BE concentrations. The level of gene-specific mRNA for the c-Ha-ras, c-fms, and c-mos genes in these cells also remained constant during exposure to BE. Ribosomal RNA is not degraded during 24 hours of BE treatment in vitro, suggesting that BE does not maintain the relative mRNA level for these genes by selective degradation of other RNA species. The inhibition of RNA and DNA synthesis by BE without a corresponding alteration in the level of expression of the c-myc gene suggests that this agent dissociates c-myc expression and cellular proliferation in these cells.

Cell Division↗
PubMed1994

The relationship of the in vivo cell cycle characteristics and treatment outcome in acute myelogenous leukemia to the expression of the FMS and MYC proto-oncogenes.

Fms expression was measured by Northern blot analysis in the pretherapy leukemia cells of 30 patients with acute myelogenous leukemia (AML) who either entered CR or who were shown to have drug resistant disease. High levels of fms expression correlated with a CR outcome and were strongly associated with the fall in the number of leukemia cells during the first six days of remission induction therapy. In contrast, similar studies of myc expression failed to demonstrate any relationship to treatment outcome. Considering those genes whose expression have been measured to date, the level of expression of fms is the one which is most highly correlated with treatment outcome in AML. No significant relationship between the expression levels of these two genes and the cell cycle characteristics of leukemia cells in vivo were detected.

Blotting, Northern↗
PubMed2004

[Detection of FLT3 gene and FLT3/ITD gene mutation in chronic myeloid leukemia and its significance].

BACKGROUND & OBJECTIVE: Fms-like tyrosine kinase 3 (FLT3)gene abnormal expression could be detected in most of acute myeloid leukemia (AML)patients, and 20%-30% of them have FLT3/ITD gene mutation which indicate poor prognosis. This study was to detect FLT3 gene expression, and FLT3/ITD gene mutation in chronic myeloid leukemia (CML)patients, and analyze their relationships with prognosis. METHODS: Polymerase chain reaction (PCR)was used to detect FLT3 gene expression, and FLT3/ITD gene mutation in 53 CML patients of chronic phase,and 34 CML patients of accelerated phase or blast crisis. RESULTS: FLT3 gene was detected in 5.7%(3/53)CML patients of chronic phase, and in 55.9% (19/34)CML patients of accelerated phase or blast crisis,the difference of FLT3 gene positive rate between these 2 groups was significant (P< 0.001). Only 2 of 87 CML patients (2.3%)were found with FLT3/ITD mutation. CONCLUSIONS: FTL3 gene expresses mainly in CML patients of accelerated phase or blast crisis. FTL3/ITD gene mutation was seldom involved in CML patients. The CML patients with FLT3 gene expression and FTL3/ITD gene mutation may have poor prognosis.

Adult↗
PubMed1991

Characterization of the 5q- breakpoint in an acute nonlymphocytic leukemia patient using pulsed-field gel electrophoresis.

Multiple genes of hematopoietic importance have been localized to the long arm of chromosome 5 including granulocytemacrophage colony stimulating factor (GM-CSF) and interleukins (IL) 3, 4 and 5 to 5q23-31, colony stimulating factor 1 (CSF1) to 5q33.1 and its receptor (c-fms) to 5q33.3. The genes coding for platelet-derived growth factor receptor (PDGFR) and acidic fibroblast growth factor (FGFA) have been localized to 5q31-32 and 5q31.3-33.2, respectively. These genes fall in the region of chromosome 5 which is deleted in the 5q- refractory anemia syndrome (5q-RA) and acute nonlymphocytic leukemia (ANLL). We have characterized this region in a 5q- patient with therapy-related ANLL (t-ANLL) by pulsed-field gel electrophoresis and Southern blotting analysis utilizing DNA probes for PDGFR, c-fms, and FGFA. A single 300 kbp M1uI restriction fragment was detected in the patient using a PDGFR probe as compared to a 200 kbp fragment in normal controls. BssHII digestions also showed restriction fragment length difference. Similar data for both M1uI and BssHII digestions were also obtained when c-fms was used as a probe. Southern blotting analysis of EcoRI-digested DNA showed that each of the PDGFR, c-fms, and FGFA alleles were deleted. These results suggested that one chromosome 5 has a large deletion involving PDGFR, c-fms and FGFA, which is consistent with the cytogenetic analysis of the patient. In contrast, the other chromosome 5, which appeared normal cytogenetically, may have a smaller deletion (or alteration) in proximity to but not involving any of these 3 genes.

Adult↗
PubMed1992

Detection of transforming oncogenes in rat colon tumors induced by direct perfusion with N-methyl-N-nitrosourea.

We assayed rat colon tumors induced by N-methyl-N-nitrosourea (MNU) for transforming oncogenes by the NIH 3T3 transfection and nude mouse tumorigenicity assays. Transfection of DNA from 3 of 3 adenomas and 3 of 5 carcinomas induced transformed foci on NIH 3T3 cells. DNA from 2 of 3 primary foci also possessed focus-forming activity, and rat-specific sequences were observed in secondary focus DNAs. Furthermore, NIH 3T3 cells transfected with DNA from a carcinoma and from a primary focus derived from it, both positive in the focus-forming assay, induced tumors in nude mice. We found no evidence for rat H-ras, K-ras, or N-ras sequences in the DNA of any of 16 primary foci derived from 6 rat tumors; thus, in contrast to other animal tumor models induced by MNU, activation of the ras genes does not appear to predominantly occur in MNU-induced rat colon tumors. We also did not observe, in any of these foci, sequences corresponding to the rat neu, raf, fms, met, or hst genes, thus indicating that none of these is the transforming oncogene in our model. These results suggest that an as yet unidentified transforming oncogene may be activated in rat colon tumors induced by MNU.

3T3 Cells↗
PubMed1992

N-formimidoyl fortimicin A synthase, a unique oxidase involved in fortimicin A biosynthesis: purification, characterization and gene cloning.

Micromonospora olivasterospora, a fortimicin A (FTM A, astromicin) producer, was found to carry an enzyme that converts FTM A to N-formimidoyl FTM A (FI-FTM A). This enzyme (FI-FTMase) was purified to homogeneity and shown to be a flavin adenine dinucleotide (FAD) enzyme. Tracer experiments proved that the formimidoyl group was derived from C-2 of glycine via oxidation of the amino acid in the presence of FTM A and oxygen. The gene encoding this enzyme, fms 14, was cloned using a 26-mer oligonucleotide probe, designed according to the N-terminal amino acid sequence of purified FI-FTMase, from a cosmid clone pGLM990, which has been shown to contain a cluster of FTM A biosynthetic genes. The nucleotide sequence, and biochemical and genetic analysis revealed that FI-FTMase is composed of four identical subunits of mol. wt. 52,000, and contains at least one FAD per subunit. DNA regions homologous to fms14 were found in two other producers of the fortimicin group of antibiotics, Dactylosporangium matsuzakiense ATCC31570 and Micromonospora sp. SF-2098.

Actinomycetales↗
PubMed1985

Expression of the human c-fms proto-oncogene in hematopoietic cells and its deletion in the 5q- syndrome.

The c-fms proto-oncogene was shown to be expressed in human bone marrow and in differentiated blood mononuclear cells, suggesting that its gene product plays a role in hematopoietic maturation. The c-fms mRNA was not detected in HL-60 cells, an established promyelocytic line, whereas c-fms expression appeared 48 hr after induction when most cells had differentiated into macrophages. An acquired deletion of chromosome 5 (5q-) in bone marrow cells is associated with abnormalities in blood cell production. The normal 5 and 5q- chromosomes were segregated by construction of cell hybrids between bone marrow and rodent cells. A selective system was used that requires retention of the structural gene for dihydrofolate reductase, located on human chromosome 5. Analysis of DNA from individual hybrid clones revealed that the 5q- deletion had removed the c-fms gene. We postulate that hemizygosity at the c-fms locus leads to abnormalities in hematopoietic maturation.

Anemia, Aplastic↗
PubMed1992

Oncogene alterations in rat colon tumors induced by N-methyl-N-nitrosourea.

The authors assayed oncogene alterations in rat colon tumors induced by the direct-acting chemical carcinogen, N-methyl-N-nitrosourea (MNU). DNA isolated from 34 adenomas and eight carcinomas, as well as adjacent normal colon, of 11 rats was assayed by Southern blotting for restriction fragment length polymorphisms and gene amplifications and deletions in 13 oncogenes known to be involved in human or other animal tumors. In addition to finding apparent point mutations or other small alterations in the fos and abl genes in individual rat colon tumors, the authors observed what appear to be larger alterations (ie, rearrangements, or intragenic insertions or deletions) in the H-ras and myb loci in several tumors. In contrast, no changes in the K-ras, N-ras, myc, N-myc, neu, raf, fms, met, and hst genes were seen in any of these tumors. The frequency of myb gene alterations was higher in carcinomas than in adenomas, suggesting that these changes occurred relatively late during tumorigenesis and were not direct effects of the carcinogen. In addition, the finding of alterations in two or three oncogenes in several MNU-induced rat colon tumors suggests the possibility of more widespread genomic lesions in this model.

Animals↗