Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective induction of programmed cell death, apoptosis, may represent a new approach to the treatment of cancer. Apoptosis can be induced by the monoclonal antibody anti-APO-1 directed against the cell surface receptor APO-1, a member of the nerve growth factor (NGF) receptor/tumor necrosis factor (TNF) receptor superfamily. We determined APO-1 expression and sensitivity to anti-APO-1 mediated apoptosis in childhood acute lymphoblastic leukemia cells of T lymphocyte precursor phenotype (T-ALL). APO-1 was constitutively expressed by 21 of 30 T-ALL and by all T-ALL cell lines investigated. However, most APO-1 positive T-ALL were resistant to anti-APO-1 mediated apoptosis. Sensitivity to anti-APO-1 mediated apoptosis was independent of the density of APO-1 expression on the cell surface and independent of the amount of Bcl-2. Incubation of resistant T-ALL with the protein synthesis inhibitor cycloheximide reversed resistance and induced sensitivity to anti-APO-1 mediated apoptosis in most T-ALL. These data suggest that resistance to anti-APO-1 mediated apoptosis in T-ALL is maintained by an active cellular program. Reversion of resistance to sensitivity towards induction of apoptosis in tumors may provide a new basis for successful therapeutic intervention.
Leukemia 1995 May
PMID:Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program. 753 14

Vascular endothelial growth factor (VEGF) has been identified as a peptide growth factor specific for vascular endothelial cells. In this study, we demonstrated the expression of the KDR gene transcript, which encodes a cell surface receptor for VEGF, in normal human hematopoietic stem cells, megakaryocytes, and platelets as well as in human leukemia cell lines, HEL and CMK86. Moreover, we showed the expression of VEGF gene transcript in these normal fresh cells and cell lines. To elucidate biological functions of VEGF on hematopoiesis, we determined whether this growth factor has mitogenic activity to hematopoietic cells or the ability to suppress apoptotic cell death. The liquid culture and colony-formation assay revealed that VEGF suppressed apoptotic cell death of both CMK86 cells and normal hematopoietic stem cells caused by gamma-ray irradiation, although mitogenic activity of VEGF was not detected. The ability of VEGF to suppress apoptotic cell death was independent of the change of cell cycle distribution. These data suggest that VEGF may play an important role in survival or maintenance of hematopoietic stem cells due to the prevention of apoptotic cell death caused by some stresses such as ionizing radiation and that VEGF may give leukemia cells some abilities of resistance against radiotherapy in an autocrine or paracrine manner.
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PMID:Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. 758 55

C5a, a potent chemoattractant for monocytes, neutrophils, and other leukocytes, binds to a cell surface receptor of the seven-transmembrane superfamily. Here we report the effects of substituting Gln for Glu199 of the human C5a receptor (hC5aR) expressed in a model cell system for chemoattractant receptor signaling, the rat basophilic leukemia cell line RBL-2H3. Both the binding affinity for hC5a and the EC50 for subsequent cellular signals are reduced 5-10-fold by this substitution. A peptide mimic of the C terminus of C5a also binds to, and activates, hC5aR. The response to this peptide is reduced in cells bearing mutated hC5aR, indicating that the mutation affects interactions with the C terminus of hC5a. The C-terminal peptide contains only two basic residues, a Lys and an Arg (assumed to be analogous to Lys68 and Arg74 of hC5a), which could act as counter-ions for Glu199 of the receptor. If the counter-ion on hC5a was Arg74, then it would be expected that intact hC5a and hC5a des-Arg74 would have identical affinities and potencies when interacting with mutant hC5aR. It was found, however, that the binding affinity and potency (for receptor signaling events) of hC5a des-Arg74 was always lower than for intact hC5a. Furthermore, the equivalent C-terminal peptide to hC5a des-Arg74 (i.e. lacking the C-terminal Arg) could partially activate the wild type but not the mutant receptor, whereas the converse peptide, containing Arg but containing Met instead of Lys, had equal potencies for both wild type and mutant receptors. Taken together these data indicate that Glu199 of hC5aR is not involved in an interaction with Arg74 of hC5a, but may interact with Lys68 of hC5a. Mutation of Glu199 defines a second ligand binding site on hC5aR, distinct from the previously characterized site on the receptor N terminus. Unlike the N-terminal binding site, this second site is associated not just with the interaction with hC5a, but also with receptor activation.
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PMID:Mutation of glutamate 199 of the human C5a receptor defines a binding site for ligand distinct from the receptor N terminus. 762 71

Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate programmed cell death.
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PMID:Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. 762 2

The gene for the cell surface receptor for HTLV-I, the etiologic agent of adult T-cell leukemia and HTLV-I-associated myelopathy, has been localized to distal human chromosome 17q. A panel of somatic cell hybrids containing fragments of human 17q as the only human genetic component was mapped with a set of 10 chromosome 17 probes and utilized to regionally localize the gene. When compared to the murine fibroblast fusion partner, L-M(TK-), and a hybrid cell line containing human chromosome 20, human 17q-containing hybrid cells bound high levels of both HTLV-I virions and the monoclonal antibody, Mab 34-23, which may be directed against the putative HTLV-I receptor. Additional experiments revealed that the human 17q-containing hybrids could also be more efficiently infected by cell-free HTLV-I virions than could the control cell lines. Western blot analyses of cell lysates showed that recombinant HTLV-I envelope gp46 protein and Mab 34-23 both bound to proteins of approximate MW 30 and 31 kDa which were found only in the hybrid cell lines which contained human chromosome 17q. The data suggest that the gene for the HTLV-I receptor is located on the distal region of human chromosome 17q demarcated by the tk-1 locus (17q23.2-17q25.3).
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PMID:Regional localization of the putative cell surface receptor for HTLV-I to human chromosome 17q23.2-17q25.3. 767 29

Gene transfer into human cells using murine amphotropic retroviral vectors is the basic technique used in most current gene therapy studies. The identity of the cell surface receptor for the amphotropic envelope remains unknown and thus its importance in gene transfer is poorly understood. We have measured specific retrovirus binding to cells to study amphotropic virus receptor regulation in human CD34+ bone marrow (BM) progenitors and primitive CD34+CD38- human hematopoietic cells. The rat monoclonal antibody 83A25 recognizes an epitope common to the envelope glycoprotein of all classes of Moloney murine leukemia virus. Indirect fluorescent labeling of 83A25 allows flow cytometric analysis of specific virus-cell interactions and is an indirect measure of specific receptors. Using this assay, amphotropic virus binding to fresh CD34+ cells was minimal. However, when CD34+ cells were cultured with or without growth factors for 4 days, specific binding of amphotropic retrovirus was readily shown. Inclusion of interleukin-3 (IL-3), IL-6, and Steel factor in cultures increased the fluorescence associated with amphotropic virus binding by twofold to four-fold (mean fold increase 2.7 +/- 0.84). Virus binding to CD34+CD38- cells was shown only in those cells culture in IL-3, IL-6, and Steel factor. These results suggest that certain cytokines may cause an increase in the number and/or affinity of amphotropic receptors on primitive human hematopoietic cells. Upregulation of viral receptor expression may be one of the mechanisms by which cytokines enhance gene transfer into primitive BM cells.
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PMID:Growth factors increase amphotropic retrovirus binding to human CD34+ bone marrow progenitor cells. 769 78

The primate type C retrovirus gibbon ape leukemia virus (GaLV) has been shown to use a widely expressed, multiple membrane-spanning protein of unknown function as its cell surface receptor on human cells (GLVR1) (Johann, S. V., Gibbons, J. J., and O'Hara, B. (1992) J. Virol. 66, 1635-1640; O'Hara, B., Johann, S. V., Klinger, H. P., Blair, D. G., Rubinson, H., Dunni, K.J., Sass, P., Vitek, S. M., and Robins, T. (1990) Cell Growth Diff. 1, 119-127). Here we present evidence that the receptor for GaLV (GLVR1) functions as a sodium-dependent transporter of inorganic phosphate. GLVR1 is shown to have approximately 3-4-fold higher affinity for phosphate than other mammalian phosphate transporters described to date. Productive infection of GLVR1-expressing cells by GaLV, but not other retroviruses, results in the complete blockade of GLVR1-specific uptake of inorganic phosphate. Since productive infection of cells with GaLV is generally not cytotoxic, it is likely that more than one phosphate transporter exists on the cell surface. Our data suggest that GLVR1 represents a sodium-dependent phosphate transporter that differs from other mammalian phosphate transporters in structure, affinity for phosphate, and function.
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PMID:The cellular receptor for gibbon ape leukemia virus is a novel high affinity sodium-dependent phosphate transporter. 792 40

Examination of the interferon gamma (IFN-gamma) amino acid sequence revealed two conserved basic amino acid clusters similar to the prototype nuclear localization signal. We followed the fate of cell surface receptor-bound IFN-gamma in murine leukemia L1210 cells. A time- and temperature-dependent accumulation of murine IFN-gamma in the cell nucleus could be demonstrated by autoradiography and indirect immunofluorescence after the rapid isolation of nuclei. Human IFN-gamma was also internalized and translocated to the nucleus of murine L1210 cells transfected with and expressing the human IFN-gamma receptor, but it appeared to be retained by the nucleus only transiently. IFN-gamma molecules chemically crosslinked to their cell surface receptor remain capable of being translocated to the nucleus even as part of a receptor-ligand complex. Thus, the bipartite nuclear localization signal sequence appears to be functional and suggests that nuclear targeting could participate in IFN-gamma signal transduction.
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PMID:Nuclear accumulation of interferon gamma. 799 44

The cell surface receptor for ecotropic host-range murine leukemia viruses is a sodium-independent transporter for essential cationic acids. Our evidence strongly identifies this receptor as the transporter system y+, which was previously characterized by transport assays. Mutational analysis indicates that transporter activity is not necessary for viral reception. Infection of cells with ecotropic retroviruses causes only a partial down-modulation of receptor expression on cell surfaces.
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PMID:Cell surface receptor for ecotropic host-range mouse retroviruses: a cationic amino acid transporter. 803 77

In this report we identify the specific isozymes of protein kinase C (PKC) that are involved in c-fos and c-jun mRNA accumulation in the rat basophilic leukemia cell line RBL-2H3. These cells could be largely depleted of the endogenous PKC isozymes by chronic treatment with phorbol 12-myristate 13-acetate followed by permeabilization of the cells with streptolysin O. The reconstitution of these cells with defined concentrations of either PKC-beta or PKC-epsilon up to 10 nM and 20 nM, respectively, induced c-fos and c-jun in a dose-dependent manner. At high concentrations of PKC-beta and -epsilon the induction of c-fos and c-jun was independent of the aggregation of the high-affinity IgE receptors (Fc epsilon type I receptors). In contrast, at limiting concentrations of these two PKC isozymes, 1 nM, the increase in c-fos and c-jun mRNAs was dependent on the aggregation of the Fc epsilon type I receptors. Unlike PKC-beta and -epsilon, PKC-alpha and PKC-delta failed to reconstitute c-fos and c-jun induction at any dose over the range examined. We conclude that PKC-beta and PKC-epsilon serve as a link between the cell surface receptor and gene expression.
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PMID:Protein kinases C-beta and C-epsilon link the mast cell high-affinity receptor for IgE to the expression of c-fos and c-jun. 805 50


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