Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for acute myeloblastic leukemia (AML) cells. Murine double minute 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), can function both to induce cell proliferation and enhance cell survival, and is frequently overexpressed in leukemias. Therefore, we focused on the importance of MDM2 protein in GM-CSF-dependent versus GM-CSF- independent growth of AML cells. The TF-1 AML cell line, which has both wtp53 and mutant p53 genes, showed GM-CSF-dependent growth; deprivation of GM-CSF resulted in G1 growth arrest and apoptosis. MDM2 mRNA and protein were highly expressed in proliferating TF-1 cells in the presence of GM-CSF and decreased significantly with deprivation of GM-CSF. In contrast, p53 protein increased with GM-CSF deprivation. Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-CSF deprivation, and is associated with decreased p53 protein expression. Moreover, a variant of TF-1 cells that grows in a GM-CSF-independent fashion also expressed high levels of MDM2 and low levels of p53. These results suggest that GM-CSF-independent growth of AML cells is associated with overexpression of MDM2 protein and related modulation of p53 expression.
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PMID:MDM2 protein overexpression inhibits apoptosis of TF-1 granulocyte-macrophage colony-stimulating factor-dependent acute myeloblastic leukemia cells. 968 Mar 65

An in vitro carcinogenesis model of human skin keratinocytes has been developed based on the spontaneously immortalized keratinocyte cell line HaCaT. Immortalization, the initial stage in human carcinogenesis in vitro, was induced by ultraviolet-type mutations in the p53 gene followed by further genetic alterations leading to the loss of senescence genes, in particular on chromosome 3p. Despite multiple genetic changes, the HaCaT cell line sustained its genomic balance up to high passage levels and maintained a non-tumorigenic phenotype. Tumorigenic transformation was induced by ras oncogene transfection but also by culture stress and elevated temperature, resulting in benign and malignant tumorigenic clones. Malignant conversion was associated with the loss of a copy of chromosome 15, leading to a decrease in thrombospondin-1 (TSP-1) expression. Heat-induced malignant conversion was associated with a gain of material on chromosome 11, including the cyclin D1 gene. The microenvironment plays a major role in tumorigenic transformation and the control of malignant cells. Overexpression of platelet-derived growth factor in HaCaT cells caused mesenchyme activation and formation of benign tumors. Halting tumor angiogenesis completely prevented invasion of malignant cells and induced a benign tumor phenotype. Transfer of a normal chromosome 15 or TSP-1 transfection into a skin carcinoma line resulted in tumor suppression due to TSP-1-blocked tumor vascularization. Because of the reduced TSP-1 expression, blood vessels infiltrated the tumor, and it expanded. Progression to more aggressive tumor phenotypes required the in vivo environment and was caused by selection of a subpopulation and further genetic modifications. The improved autonomous growth of these cells was associated with new expression of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which acted in an autocrine manner to stimulate proliferation and migration. With this in vitro skin carcinogenesis model we were able to demonstrate multiple stages in the transformation process that were associated with different genetic and phenotypic characteristics. In addition, we documented that modulation of the tumor stroma plays an important and decisive role in tumor development and progression. From this we hypothesize that the growth restraints of the microenvironment are increasingly lost with advancing stages of carcinogenesis but can be restored by modulation of the tumor stroma.
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PMID:Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. 983 75

Gene therapy encompasses deliberate alteration of the genetic material of cancer cells. Somatic-cell therapy involves the administration to cancer patients of living cells that have been genetically manipulated or processed to change their biological characteristics. Gene therapy of cancer, although much hyped, is still in its very early infancy. Current approaches to delivering genes into cells include physico-chemical methods, viral vectors and direct DNA injection. None of these strategies is in any way perfect and their efficacy leaves much to be desired. Based on the somatic mutation theory of carcinogenesis, it would be attractive to repair genetic alterations responsible for neoplastic transformation and clonal evolution of cancer cells. Attempts have been made to replace inactivated tumour suppressor genes in cancer cells through intact wild type gene copies, or to suppress the leukaemogenic effects of chromosomal fusion genes in leukaemia through antisense oligonucleotides. One of the snags of these concepts is that cancer cells harbour several if not myriads of mutated genes, and clonal tumour heterogeneity seems to be the rule rather than the exception. It is at present impossible to repair all gene mutations in cancer lesions of a given patient if such were to be the aim of therapy. Nevertheless, some interesting clinical data have been reported. These include the local injection via bronchoscopy of p53 wild type gene copies into p53-deficient lung cancer lesions and other tumours. Somatic-cell therapy includes a considerable spectrum of interventions. Tumour cells may be transduced with genes which upon their expression will render the tumour cells more immunogenic. Tumour-infiltrating lymphocytes may be harvested, transduced with a gene of interest and re-injected. Since they recognise tumours specifically, they will serve as vehicles to carry therapeutic genes into cancer lesions where the gene product can exert an anti-cancer effect. Such attempts might increase the immunogenicity of tumours considerably. Examples are the transduction of tumour-infiltrating lymphocytes with a gene for tumour necrosis factor alpha or the transduction of tumour cells with the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic renal cell carcinoma. Protocols on gene therapy and somatic-cell therapy seem to be a worthy goal of cancer research. However, it seems unlikely that gene therapy will provide magic anti-cancer bullets in the near future or the definitive cancer cure, although this is often promised in the media. Careful clinical and laboratory research will pave the way towards stepwise improvement of cancer patient care.
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PMID:[Molecular therapy in malignant tumors]. 1060 49

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains viability of the mouse interleukin (IL)-3 dependent lymphoid cell line BA/F3 expressing the hGM-CSF receptor. Caspase-3 like enzyme activity and DNA fragmentation were augmented by depletion of this factor from the cell, and exposure to gamma irradiation accelerated kinetics of these events. Anti gamma irradiation-induced apoptosis occurred through various mutant GM-CSF receptors and only the box1 region was essential while the C terminal region, including tyrosine residues which are required for MAPK cascade activation, was dispensable. Consistent with this notion, the addition of PD98059 had no effect on this activity thereby indicating that activation of MAPK is not essential for the activity. As expected, gamma irradiation increased p53 protein and bax mRNA levels and the presence of hGM-CSF dramatically modulated bax/bcl-X(L) ratio. The PI-3K specific inhibitor wortmannin did not affect hGM-CSF dependent anti gamma irradiation induced apoptosis nor bcl-X(L) induction, thus bcl-X(L) but not PI-3K pathway seems to be involved in hGM-CSF dependent anti gamma irradiation-induced apoptosis. It is well documented that the boxl region is essential for GM-CSF dependent activation of JAK2 and JAK2 specific inhibitor AG490 suppressed anti gamma, irradiation-induced apoptosis by hGM-CSF. An artificial JAK2 activating molecule in which extracellular and the transmembrane of beta(c) fused with whole JAK2 can sustain BA/F3 cells survival and proliferation mIL-3 independently, but these cells are susceptible to gamma irradiation. Furthermore GyrB/Jak2, which can activate STAT5 but not the MAPK cascade nor survival of BA/F3 cells, also could not prevent gamma irradiation-induced apoptosis. Although JAK2 is essential for hGM-CSF dependent anti gamma irradiation-induced apoptosis, it appeared that JAK2 does not seem sufficient for the activity.
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PMID:Analysis of mechanisms involved in the prevention of gamma irradiation-induced apoptosis by hGM-CSF. 1069 27

Co-transfer of immunomodulatory and anti-proliferative genes may be the basis for new strategies to enhance tumor regression. The purpose of this study was to develop a combination gene therapy strategy for the treatment of laryngeal cancer. Human wild-type p53 and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes were transferred into human laryngeal cancer cells mediated by adenovirus type 5 vector co-expressing human wild-type p53 and GM-CSF (Ad-p53/GM-CSF). By the introduction of the wild-type p53 gene, the growth of human laryngeal cancer Hep-2 cells was inhibited and their apoptosis was induced. By the introduction of the GM-CSF gene, the immunogenicity of cancer cells was enhanced. Significant proliferation of tumor infiltrating lymphocytes and tumor-specific cytotoxicity of cytotoxic T lymphocytes were induced by Ad-p53/GM-CSF-infected cancer cells in vitro. The results suggest that the co-transfer of human wild-type p53 and GM-CSF genes into tumor cells via recombinant adenovirus may be further developed into an effective and practical combination gene therapy strategy for laryngeal cancer.
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PMID:Co-transfer of human wild-type p53 and granulocyte-macrophage colony-stimulating factor genes via recombinant adenovirus induces apoptosis and enhances immunogenicity in laryngeal cancer cells. 1132 95

Gene alterations accumulate during the progression of acute myelogenous leukemia (AML) to a malignant clone. Here, a new myeloid cell line, designated YSK-21, with the balanced t(8;21)(q22;q22) and the unbalanced der(1)t(1;17)(p36;q21), was established. YSK-21 grows well in a medium containing recombinant human granulocyte colony-stimulating factor (rhG-CSF), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), or interleukin-3 (rhIL-3). Molecular analysis using the reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) revealed that t(8;21)(q22;q22) resulted in an AML1-MTG8 fusion transcript. FISH and spectral karyotyping (SKY) in conjunction with G-banding analysis revealed a der(1)t(1;17)(p36;q21) chromosomal translocation, which appeared in the clone developed from the original leukemic cells. Molecular analysis of the TP73 gene on 1p36 and the TP53 gene revealed a deletion of one-allele in TP73 with partial demethylation of another allele in the initial clone of YSK, and a point mutation consisting of an A-->T substitution in codon 288 of the TP53 gene in the developed clone of YSK-21. YSK-21 cells, expressing aberrant AML1-MTG8, TP53, and TP73 protein molecules, may be useful for elucidating the pathophysiology of these aberrant proteins and for studying the der(1)t(1;17)(p36;q21) chromosomal translocation.
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PMID:Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia. 1155 Feb 87

Multi-drug resistance can be induced by various environmental stresses including an exposure to chemical drugs and X-ray irradiation. In addition, hypo-nutritive conditions are known to promote multi-drug resistance in solid tumours. To understand the importance of nutritive conditions in the development of drug resistance in non-solid tumours and to know whether a transient malnutrition could induce a permanent reduction in drug sensitivity, leukaemic cells were transiently cultured under growth factor-starved conditions. Granulocyte-macrophage colony-stimulating factor-dependent human leukaemic MO7e cells were cultured in the absence of granulocyte-macrophage colon-stimulating factor for 2 weeks, during which the majority of the cells died, and the minor viable cells were expanded in the presence of granulocyte-macrophage colon-stimulating factor for following 1 week. This procedure was repeated three times, and the surviving cells were cloned by limiting dilution. These clones underwent G1 arrest in the absence of granulocyte-macrophage colon-stimulating factor, while parental cells underwent apoptosis. Interestingly, activities of the downstream targets of granulocyte-macrophage colon-stimulating factor receptor were regulated in a granulocyte-macrophage colon-stimulating factor-independent manner, indicating that the ligand-independent activation of granulocyte-macrophage colon-stimulating factor receptor had not taken place. Moreover, the 4--7-fold increases in IC(50) for etoposide and the 2--6-fold increase in IC(90) for doxorubicin was observed. Furthermore, Bcl-2 protein expression was significantly up-regulated in the clones while no significant changes in Bax, Bcl-(xL), P-glycoprotein and Hsp70 protein expression and no consistent changes in p53 expression were detected. We propose that recurrent growth factor starvation, which may occur in vivo when stromal function is damaged after intensive chemotherapy or bone marrow occupation by malignant cells, causes selection of drug resistant leukaemia cells that will expand when the growth factor supply recovers.
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PMID:Recurrent growth factor starvation promotes drug resistance in human leukaemic cells. 1187 May 22

Co-transfer of immunomodulatory and antiproliferative genes may be the basis for new strategies to potentiate tumor regression. In this study, we evaluated the in vitro effect of the introduction of human wild-type p53, granulocyte-macrophage colony-stimulating factor (GM-CSF), and B7-1 genes via recombinant adenovirus on the growth and immunogenicity of Hep-2 or primary laryngeal cancer cells. By the introduction of wild-type p53 gene, the growth of Hep-2 cells was inhibited via enhanced apoptosis. By the introduction of GM-CSF and B7-1 genes, the immunogenicity of cancer cells was enhanced. Significant proliferation of tumor infiltrating lymphocytes (TILs) and tumor-specific cytotoxicity of cytotoxic T lymphocytes (CTLs) were induced in vitro. Furthermore, the combinative effect of GM-CSF and B7-1 was even more evident than that of any one of them singly. These results suggest that the co-transfer of human wild-type p53, GM-CSF and B7-1 genes into tumor cells via recombinant adenovirus may be further developed into a potential combination gene therapy strategy for cancer.
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PMID:Growth suppression and immunogenicity enhancement of Hep-2 or primary laryngeal cancer cells by adenovirus-mediated co-transfer of human wild-type p53, granulocyte-macrophage colony-stimulating factor and B7-1 genes. 1204 60

We established a new lung cancer cell line, designated Y-ML-1B, from a lung cancer of a 70-year-old Japanese man with leukocytosis and thrombocytosis. Before surgical resection, the white blood cell and platelet counts were elevated to 34,400/mm3 and 668,000/mm3, respectively, and the granulocyte colony-stimulating factor (G-CSF) level in the serum was increased at 141 pg/mL. The primary tumor showed an undifferentiated morphology with large cells and induced extensive thickening of the pleura in the right hemithorax. The Y-ML-1B cells grow as a monolayer, with a doubling time of 19 hours, and are tumorigenic in nude mice, which showed a morphology similar to the primary tumor in xenografts. Analysis of the supernatant of cell culture medium of Y-ML-1B showed elevated levels of G-CSF and other cytokines such as interleukin (IL)-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF), consistent with the high levels detected in the patient's serum. Cytogenetic analysis revealed aneuploidy of greater than 56 in metaphases with many structural abnormalities. Mutation analysis of the tumor suppressor genes showed that Y-ML-1B is inactivated in TP53 and RASSF1A, but not in p14(ARF), p16(INK4A), or RB. Neither activating mutations of KRAS or NRAS nor amplification of MYC or MDM2 were detected. Y-ML-1B expressed N-cadherin but not E-cadherin. This newly established cell line might serve as a useful model for studying the molecular pathogenesis for large cell cancers of the lung which express high levels of cytokines.
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PMID:Establishment of a large cell lung cancer cell line (Y-ML-1B) producing granulocyte colony-stimulating factor. 1237 11


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