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PubMedDate not supplied

Partial characterization of an immortalized human trophoblast cell-line, TCL-1, which possesses a CSF-1 autocrine loop.

Many previous studies in both mouse and human placenta have implicated a role for colony stimulating factor-1 (CSF-1) in the regulation of placental development. In this study we have examined CSF-1 production by an immortalized cell line (TCL-1) derived from the choriodecidua, transfected with a retrovirus gene coding for the large-T antigen. TCL-1 cells were uniformly positive by immunocytochemistry for the composite sub-units of human chorionic g gonadotrophin (hCG) but were negative for markers of other cell types localized at the fetal-maternal interface. Gelatinase enzymes were secreted by TCL-1 cells cultured on extracellular matrix in a manner indicative of extra-villous trophoblast. Dot-blot immunoassays and ELISA indicated that CSF-1 was secreted by TCL-1 cells, at levels comparable to primary trophoblast cells and BeWo choriocarcinoma (trophoblast tumour) cells. Reverse transcriptase-polymerase chain reaction analysis confirmed the presence in TCL-1 cells of CSF-1 receptor mRNA (c-fms gene product), indicating that the components of a potential autocrine loop were present in these cells. Proliferation of TCL-1 cells was not affected by the addition of exogenous CSF-1 but was elevated in response to treatment with a CSF-1 neutralizing antibody. The immortalized cell line, TCL-1, provides a potential model in which to investigate regulation of growth and differentiation of trophoblast cells in vitro.

Base Sequence↗
PubMed1996

Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.

The Ras oncogene products regulate the expression of genes in transformed cells, and members of the Ets family of transcription factors have been implicated in this process. To determine which Ets factors are the targets of Ras signaling pathways, the abilities of several Ets factors to activate Ras-responsive enhancer (RRE) reporters in the presence of oncogenic Ras were examined. In transient transfection assay, reporters containing RREs composed of Ets-AP-1 binding sites could be activated 30-fold in NIH 3T3 fibroblasts and 80-fold in the macrophage-like line RAW264 by the combination of Ets1 or Ets2 and Ras but not by several other Ets factors that were tested in the assay. Ets2 and Ras also superactivated an RRE composed of Ets-Ets binding sites, but the Ets-responsive promoter of the c-fms gene was not superactivated. Mutation of a threonine residue to alanine in the conserved amino-terminal regions of Ets1 and Ets2 (threonine 38 and threonine 72, respectively) abrogated the ability of each of these proteins to superactivate reporter gene expression. Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein. The Ras-dependent increase in threonine phosphorylation was not observed in Ets2 proteins that had the conserved threonine 72 residue mutated to alanine or serine. These data indicate that Ets1 and Ets2 are specific nuclear targets of Ras signaling events and that phosphorylation of a conserved threonine residue is a necessary molecular component of Ras-mediated activation of these transcription factors.

Amino Acid Sequence↗
PubMed1994

Differential expression of protooncogenes in human germ cell tumors of the testis.

BACKGROUND: It has been suggested that tumorigenesis of the germ cell tumor of the testis includes abnormal and developmentlike differentiation of primordial germ cells to several mature type tumors. METHODS: To clarify roles of protooncogenes in the unique tumorigenic mechanism in the human germ cell tumor, the authors examined the expression of 15 protooncogenes in human primary germ cell tumors of the testis with Northern blot analyses. RESULTS: Fifteen (94%) of 16 seminomas and 5 (83%) of 6 embryonal carcinomas had a significant levels of N-myc expression, whereas they did not express two receptor type protooncogenes, c-erbB-1 and c-erbB-2. In contrast, some immature teratomas had a high level of c-erbB-1 expression, and an advanced case showed a significant level of c-erbB-2 expression. Immature teratomas did not show N-myc expression. Higher levels of c-mos expression were observed in several cases of seminomas and embryonal carcinomas. Expression of c-Ki-ras or N-ras was observed in all histologic subgroups and normal testes. CONCLUSION: A significant level of N-myc expression may be essential for undifferentiated tumors including seminoma and embryonal carcinoma, whereas c-erbB-1 and possibly c-erbB-2 may have important roles in the differentiated tumors such as immature teratoma. These results suggest that some of the protooncogene expression may be switched critically during the differentiation from seminomas or embryonal carcinomas to the more differentiated-type tumor.

Biomarkers, Tumor↗
PubMed1990

Signal-response coupling mediated by the transduced colony-stimulating factor-1 receptor and its oncogenic fms variants in naive cells.

Colony-stimulating factor-1 (CSF-1 or M-CSF) supports the proliferation and survival of mononuclear phagocytes by binding to a receptor (CSF-1R) encoded by the c-fms proto-oncogene. Whereas the CSF-1R kinase is normally regulated by ligand, receptors bearing 'activating mutations' act constitutively as enzymes and can transform fibroblasts and haemopoietic cells of different lineages. Introduction of human CSF-1R enables mouse NIH-3T3 cells to form colonies in agar in response to human CSF-1 and to proliferate in serum-free medium supplemented with CSF-1, albumin, transferrin and insulin. Similarly, expression of human CSF-1R in interleukin 3-dependent mouse FDC-P1 myeloid cells enables them to grow in CSF-1. High levels of CSF-1R expression in FDC-P1 cells can induce factor-independent growth which is abrogated by a 'neutralizing' monoclonal antibody to the receptor. Therefore, critical mutations in the c-fms gene or overexpression of CSF-1R in immature myeloid precursors might each contribute to leukaemia.

Animals↗
PubMed1989

Phospholipase C-gamma, a substrate for PDGF receptor kinase, is not phosphorylated on tyrosine during the mitogenic response to CSF-1.

Quiescent mouse NIH3T3 cells expressing a transduced human c-fms gene encoding the receptor for colony stimulating factor-1 (CSF-1) were stimulated with mitogenic concentrations of platelet-derived growth factor (PDGF) or CSF-1. Immunoprecipitated phospholipase C-gamma (PLC-gamma) was phosphorylated on tyrosine and calcium was mobilized following treatment of intact cells with PDGF. In contrast, only trace amounts of phosphotyrosine were incorporated into PLC-gamma and no intracellular calcium signal was detected after CSF-1 stimulation. Similarly, CSF-1 treatment did not stimulate phosphorylation of PLC-gamma on tyrosine in a CSF-1-dependent. SV40-immortalized mouse macrophage cell line that expresses high levels of the CSF-1 receptor. In fibroblasts, antiserum to PLC-gamma co-precipitated a fraction of the tyrosine phosphorylated form of the PDGF receptor (PDGF-R) after ligand stimulation, implying that phosphorylated PDGF-R and PLC-gamma were associated in a stable complex. Pre-treatment of cells with orthovanadate also led to tyrosine phosphorylation of PLC-gamma which was significantly enhanced by PDGF, but not by CSF-1. Thus, although the PDGF and CSF-1 receptors are structurally related and appear to be derived from a single ancestor gene, only PDGF-induced mitogenesis in fibroblasts correlated with tyrosine phosphorylation of PLC-gamma.

Animals↗
PubMedDate not supplied

Regulation of hematopoietic cell function by protein tyrosine kinase-encoding oncogenes, a review.

Tyrosine phosphorylation of proteins by protein tyrosine kinases (PTKs) is an important mechanism in the regulation of various cellular processes such as proliferation, differentiation, and transformation. Accumulating data implicate PTKs as essential intermediates in the transduction of extracellular signals to the interior of the cell. This review summarizes the mechanism of action of PTKs from the major subclasses and the involvement of PTK-encoding oncogenes in the regulation of hematopoietic cell function.

Cell Differentiation↗
PubMed1992

Rare point mutation at codon 301 and 969 of FMS/M-CSF receptor in acute myelomonocytic and monocytic leukemia.

We have investigated whether point mutations occurred at codon 301 or 969 of FMS (M-CSF receptor) in 19 patients with acute myelomonocytic (M4) and monocytic leukemia (M5). Nineteen peripheral blood and bone marrow blood samples collected from M4 and M5 patients were examined by using polymerase chain reaction and hybridization to allele specific oligonucleotide probes. Mutations at codon 301 and 969 of FMS were not detected in any samples. FMS gene mutations at codon 301 and 969 were rarely involved in M4 and M5 patients in Japan.

Amino Acid Sequence↗
PubMed1995

Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor.

A paradigm has been established whereby mutant tyrosine kinase receptors such as the v-erbB and v-fms gene products function as oncoproteins in the absence of ligand. A spontaneously occurring deletional mutant of the human epidermal growth factor receptor (EGFR-vIII) has been isolated from astrocytic neoplasms and transforms NIH3T3 cells in the absence of ligand. The EGFRvIII is constitutively complexed with the majority of cellular GRB2, suggesting a link to the Ras-Mitogen-activated protein (MAP) kinase pathway (D. Moscatello, R. B. Montgomery, P. Sundareshan, H. McDanel, M. Y. Wong, and A. J. Wong, submitted for publication). In this report, we document that expression of EGFRvIII in fibroblasts is associated with downstream activation of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (MEK) and modest activation of p42 and p44 MAP kinases. The presence of EGFRvIII suppresses activation of p42 and p44 MAP kinases by phorbol 12-myristate 13-acetate (PMA) and serum; however, MEK activation by PMA is not suppressed by EGFRvIII. Basal and PMA-stimulated MAP kinase activity in EGFRvIII-transfected cells is augmented by the tyrosine phosphatase inhibitor sodium vanadate. EGFR-vIII is capable of transducing downstream signals through MAP kinase as evidenced by activation of cytoplasmic phospholipase A2 at levels similar to that induced by intact EGFR. Our results suggest that EGFR-vIII constitutively activates downstream signal transduction through MAP kinase, and this chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal.

3T3 Cells↗
PubMed1986

Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders.

By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.

Anemia, Refractory↗
PubMed2002

Human monocytic cell lines transformed in vitro by Epstein-Barr virus display a type II latency and LMP-1-dependent proliferation.

Epstein-Barr virus (EBV) classically infects and transforms B lymphocytes in vitro, yielding lymphoblastoid cell lines (LCLs). In contrast to other herpesviruses, EBV is not described as an infectious agent for monocytes. However, recent papers described in vitro infection of monocytes leading to abortive or transient viral expression. In the present study, we report the characterization of E1, a monocytic cell line infected and transformed by EBV. This cell line was derived from an LCL by a drastic electroporation and selection of neomycin-resistant cells, unfavorable to B-cell outgrowth. E1 expressed surface molecules of monocytic lineage (CD14, major histocompatibility complex class II, and CD80) and the c-fms gene, a highly specific marker for the monocytic lineage. This cell line is able to phagocytose and secrete proinflammatory monokines tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-8. E1 cells are tumorigenic after injection in nude mice, and a monocytic cell line obtained from one of these tumors (TE1) displayed immunophenotype and functional properties similar to those of E1. We detected the presence of the EBV genome in both cell lines, as well as expression of the EBNA-1 and LMP-1, but not EBNA-2, viral genes, characteristic of a type II latency. LMP-1 influences the phenotype of these monocytic cell lines, as demonstrated by down-regulation of cell proliferation and membrane intercellular adhesion molecule 1 expression due to an LMP-1 antisense strategy. This is the first description of a latently infected human monocytic cell line and the first direct demonstration of an instrumental role for LMP-1 in the proliferation of EBV-transformed cell lines expressing a type II latency.

Animals↗
PubMed2002

Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells.

Osteoclasts are derived from hematopoietic precursor cells belonging to the monocyte/macrophage lineage. Osteoclast development has been reported to be regulated by several molecules such as macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), and a decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated that the Notch signaling pathway regulates myeloid differentiation and antagonizes cell fate determination, however, the effect of Notch signaling on the osteoclast lineage has not been reported. In this study, we examined the effect of signaling via Notch receptors on the differentiation into osteoclasts by using cells from the bone marrow, spleen, and peritoneal cavity, and a cloned macrophagelike cell line. Osteoclastogenesis was inhibited by an immobilized Notch ligand, Delta-1. The dish-adherent bone marrow cells precultured with M-CSF expressed both Mac-1 and M-CSF receptors, c-Fms; osteoclastogenesis of these cells was efficiently inhibited. The immobilized Delta-1 also down-regulated the surface c-Fms expression, while the c-Fms gene expression was not changed. Genes for Notch receptors and Notch ligands are expressed in not only hematopoietic cells but also stromal cells that support osteoclast development. Constitutively active Notch1-transfected stromal cells showed increased expression of RANKL and OPG genes, and strong inhibition of M-CSF gene expression, resulting in reduction of their ability to support osteoclast development. Taken together, these findings indicate that Notch signaling affects both osteoclast precursors and stromal cells and thereby negatively regulates osteoclastogenesis.

Animals↗
PubMed2006

The JNK are important for development and survival of macrophages.

We report in this study that activation of the JNK by the growth factor, CSF-1 is critical for macrophage development, proliferation, and survival. Inhibition of JNK with two distinct classes of inhibitors, the pharmacological agent SP600125, or the peptide D-JNKI1 resulted in cell cycle inhibition with an arrest at the G(2)/M transition and subsequent apoptosis. JNK inhibition resulted in decreased expression of CSF-1R (c-fms) and Bcl-x(L) mRNA in mature macrophages and repressed CSF-1-dependent differentiation of bone marrow cells to macrophages. Macrophage sensitivity to JNK inhibitors may be linked to phosphorylation of the PU.1 transcription factor. Inhibition of JNK disrupted PU.1 binding to an element in the c-fms gene promoter and decreased promoter activity. Promoter activity could be restored by overexpression of PU.1. A comparison of expression profiles of macrophages with 22 other tissue types showed that genes that signal JNK activation downstream of tyrosine kinase receptors, such as focal adhesion kinase, Nck-interacting kinase, and Rac1 and scaffold proteins are highly expressed in macrophages relative to other tissues. This pattern of expression may underlie the novel role of JNK in macrophages.

Animals↗
PubMed1999

[Molecular biology of ovarian cancer].

It has been suggested that the accumulation in multiple steps of gene abnormality is related to the malignant transformation of the normal cell. Understanding such abnormalities would be useful in the establishment of effective measures for the early detection and treatment of cancers with poor prognoses. In gynecological malignancies, the prognosis for epithelial ovarian cancer is poor even though great numbers of patients are treated with multimodal therapy. Uncovering the genes associated with the epithelial ovarian cancer crisis could lead to the identification of high risk cases, and accurate screening could open the way to early detection. Among the genes searched to date for abnormalities related to ovarian cancer, BRCA1 is thought to be the most likely candidate for having a causal relation with the familial ovarian cancer syndrome.

BRCA1 Protein↗
PubMed1990

Human colony-stimulating factor 1 (CSF-1) receptor confers CSF-1 responsiveness to interleukin-3-dependent 32DC13 mouse myeloid cells and abrogates differentiation in response to granulocyte CSF.

Interleukin-3 (IL-3)-dependent mouse myeloid 32DC13 cells differentiate to neutrophils in response to granulocyte colony-stimulating factor (G-CSF). Introduction of the human c-fms gene, which encodes the receptor for CSF-1, into 32DC13 cells gave rise to variants that were able to proliferate in medium containing either murine IL-3 or human recombinant CSF-1, but were unable to differentiate to granulocytes in response to G-CSF. Unlike parental 32CD13 cells, CSF-1-responsive derivatives expressed nonspecific esterase when grown in CSF-1, but did not exhibit many other morphologic, immunologic, or functional properties of mononuclear phagocyte differentiation, or express murine CSF-1 receptors. 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. Although both CSF-1 and IL-3 induced tyrosine phosphorylation of heterologous substrates in the dually responsive cells, differences in the patterns of substrate phosphorylation were observed in response to the two hematopoietins. We conclude that expression of the human CSF-1 receptor in 32DC13 cells not only induces CSF-1 responsiveness, but alters its phenotype in a way that prohibits granulocyte differentiation.

Animals↗