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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different populations of wild mice (Mus musculus domesticus) in Los Angeles and Ventura Counties were observed over their lifespan in captivity for expression of infectious murine leukemia virus (MuLV) and murine mammary tumor virus (MMTV) and for the occurrence of cancer and other diseases. In most populations of feral mice these indigenous retroviruses were infrequently expressed and cancer seldom occurred until later in life (> 2 years old). MMTV was found in the milk of about 50% of wild mice, but was associated with only a low incidence (> 1%) of breast cancer after one year of age. By contrast, in several populations, most notably at a squab farm near Lake Casitas (LC), infectious MuLV acquired at birth via milk was highly prevalent, and the infected mice were prone to leukemia and a lower motor neuron paralytic disease after one year of age. These two diseases were both caused by the same infectious (ecotropic) strain of MuLV and were the principal cause of premature death in these aging LC mice. A dominant gene called FV-4R restricting the infection with ecotropic MuLV was found segregating in LC mice. Mice inheriting this FV-4R allele were resistant to the ecotropic MuLV associated lymphoma and paralysis. The FV-4R allele represents a defective endogenous MuLV provirus DNA segment that expresses an ecotropic MuLV envelope-related glycoprotein (gp70) on the cell surface. This FV-4R encoded gp70 presumably occupies the receptor for ecotropic MuLV and blocks entry of the virus. The FV-4R gene was probably acquired by the naturally occurring crossbreeding of LC feral mice with another species of feral mice (Mus castaneus) from Southeast Asia. The FV-4R gp70 does not block entry of the amphotropic MuLV that uses a separate cell surface receptor. Therefore LC mice continued to be susceptible to the highly prevalent but weakly lymphogenic and nonparalytogenic amphotropic strain of MuLV. The study points out the potential of feral populations to reveal genes associated with specific disease resistance.
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PMID:Genetic control of retroviral disease in aging wild mice. 812 69

We demonstrate that three integral membrane receptors of mammals--the ecotropic retroviral leukemia receptor (ERR), the human retroviral receptor (HRR), and the T-cell early activator (Tea)--are homologous to a family of transporters specific for amino acids, polyamines, and choline (APC), which catalyze solute uniport, solute:cation symport, or solute:solute antiport in yeast, fungi, and eubacteria. Interestingly, the ERR membrane protein was recently shown to function as a cation:amino acid cotransporter. A binary sequence similarity matrix and an evolutionary tree of the 14 members of this family, illustrating their sequence similarities and divergences, were constructed. Other proteins, including the developmentally controlled GerAII spore germination protein of Bacillus subtilis and the acetylcholine receptor of Drosophila melanogaster gave sequence comparison scores of a sufficiently large magnitude to suggest (but not to establish) a common evolutionary origin with members of the APC family. We report an extended and corrected Tea cDNA sequence and show that the mammalian Tea and ERR encoding genes are differentially expressed in tissues and cell lines. Furthermore, the two mammalian cDNA sequences hybridize with other vertebrate and yeast genomic DNAs under stringent conditions. These observations support the notion that cell surface receptor proteins in mammals are transport proteins that share a common origin with transport proteins of single-celled organisms. Thus, permeases of essential metabolites may function pathologically as viral receptors.
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PMID:Mammalian integral membrane receptors are homologous to facilitators and antiporters of yeast, fungi, and eubacteria. 838 89

The three type C retroviruses, gibbon ape leukemia virus (GALV), simian sarcoma-associated virus (SSAV), and feline leukemia virus subgroup B (FeLV-B), infect human cells by interacting with the same cell surface receptor, GLVR1. Using LacZ retroviral pseudotypes and murine cells transfected with mutant GLVR1 expression vectors, we show that the same 9-amino-acid region of human GLVR1 is critical for infection by the three viruses. Rat cells were not susceptible to infection by LacZ (FeLV-B) pseudotypes because of a block at the receptor level. We found multiple amino acid differences from human GLVR1 in the 9-amino-acid critical region of rat GLVR1. Expression of a human-rat chimeric GLVR1 in murine cells demonstrated that rat GLVR1 could function as a receptor for GALV and SSAV but not for FeLV-B. Substitution of human GLVR1 amino acids in the critical region of rat GLVR1 identified three amino acids as responsible for resistance to FeLV-B infection; two of these affect SSAV infection, but none affects GALV infection.
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PMID:Mutation of amino acids within the gibbon ape leukemia virus (GALV) receptor differentially affects feline leukemia virus subgroup B, simian sarcoma-associated virus, and GALV infections. 841 76

Human immunodeficiency virus (HIV) type 2, the second AIDS-associated human retrovirus, differs from HIV-1 in its natural history, infectivity, and pathogenicity, as well as in details of its genomic structure and molecular behavior. We report here that HIV-2 inhibits the replication of HIV-1 at the molecular level. This inhibition was selective, dose-dependent, and nonreciprocal. The closely related simian immunodeficiency provirus also inhibited HIV-1. The selectivity of inhibition was shown by the observation that HIV-2 did not significantly downmodulate the expression of the unrelated murine leukemia virus; neither did the murine leukemia virus markedly affect HIV-1 or HIV-2 expression. Moreover, while HIV-2 potently inhibited HIV-1, the reverse did not happen, thus identifying yet another and remarkable difference between HIV-1 and HIV-2. Mutational analysis of the HIV-2 genome suggested that the inhibition follows a complex pathway, possibly involving multiple genes and redundant mechanisms. Introduction of inactivating mutations into the structural and regulatory/accessory genes did not render the HIV-2 provirus ineffective. Some of the HIV-2 gene defects, such as that of tat and rev genes, were phenotypically transcomplemented by HIV-1. The HIV-2 proviruses with deletions in the putative packaging signal and defective for virus replication were effective in inducing the suppressive phenotype. Though the exact mechanism remains to be defined, the inhibition appeared to be mainly due to an intracellular molecular event because it could not be explained solely on the basis of cell surface receptor mediated interference. The results support the notion that the inhibition likely occurred at the level of viral RNA, possibly involving competition between viral RNAs for some transcriptional factor essential for virus replication. Induction of a cytokine is another possibility. These findings might be relevant to the clinical-epidemiological data suggesting that infection with HIV-2 may offer some protection against HIV-1 infection.
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PMID:Human immunodeficiency virus (HIV) type 2-mediated inhibition of HIV type 1: a new approach to gene therapy of HIV-infection. 863 95

Cyclophilin A (CyPA) is incorporated into human immunodeficiency virus type 1 (HIV-1) virions via contact with the Gag polyprotein. Genetic or pharmacologic disruption of CyPA incorporation causes a quantitative reduction in virion infectivity with no discernible effects on virion assembly or on endogenous reverse transcriptase activity. Instead, the reduction of virion-associated CyPA is accompanied by a parallel, quantitative decrease in the initiation of viral DNA synthesis after infection of T cells. The infectivity of CyPA-deficient virions is not restored by pseudotyping with Env of amphotropic murine leukemia virus, demonstrating that CyPA is not required for the HIV-1-Env-CD4 interaction. These results indicate that CyPA is required for an early step in the HIV-1 life cycle following receptor binding and membrane fusion but preceding reverse transcription. CyPA is the first cellular protein other than the cell surface receptor shown to be required for an early event in the life cycle of a retrovirus.
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PMID:Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. 864 89

The cell surface receptor for ecotropic host-range (infection limited to mice or rats) murine leukemia viruses (MuLVs) is the widely expressed system y+ transporter for cationic amino acids (CAT-1). Like other retroviruses, ecotropic MuLV infection eliminates virus-binding sites from cell surfaces and results in complete interference to superinfection. Surprisingly, infection causes only partial (ca 40 to 60%) loss of mouse CAT-1 transporter activity. The NIH/Swiss mouse CAT-1 (mCAT-1) contains 622 amino acids with 14 hydrophobic potential membrane-spanning sequences, and it is known that the third extracellular loop from the amino terminus is required for virus binding. Although loop 3 is hypervariable in different species and mouse strains, consistent with its proposed role in virus-host coevolution, loop 3 sequences of both susceptible and resistant species contain consensus sites for N-linked glycosylation. Both of the consensus sites in loop 3 of mCAT-1 are known to be glycosylated and to contain oligosaccharides with diverse sizes (J. W. Kim and J. M. Cunningham, J. Biol. Chem. 268:16316-16320, 1993). We confirmed by several lines of evidence that N-linked glycosylation occludes a potentially functional virus-binding site in the CAT-1 protein of hamsters, thus contributing to resistance of that species. To study the role of receptor glycosylation in animals susceptible to infection, we eliminated loop 3 glycosylation sites by mutagenesis of an mCAT-1 cDNA clone, and we expressed wild-type and mutant receptors in mink fibroblasts and Xenopus oocytes. These receptors had indistinguishable transport properties, as determined by kinetic and voltage-jump electrophysiological studies of arginine uptake in oocytes and by analyses Of L-[3H]arginine uptake in mink cells. Bindings of ecotropic envelope glycoprotein gp7O to the accessible receptor sites on surfaces of mink cells expressing wild-type or mutant mCAT-1 were not significantly different in kinetics or in equilibrium affinities (i.e., K(D) approximately 3.7 X 10(-10) to 7.5 X 10(-10) M). However, when values were normalized to the same levels of mCAT-1 transporter expression, cells with wild-type glycosylated mCAT-1 had only approximately 50% as many sites for gp70 binding as cells with unglycosylated mCAT-1. Although infection with ecotropic MuLV had no effect on activity of the mink CAT-1 transporter that does not bind virus, it caused partial down-modulation of wild-type mCAT-1 and complete down-modulation of unglycosylated mutant mCAT-1. These results suggest that N-linked glycosylation causes wild-type mCAT-1 heterogeneity and that a significant proportion is inaccessible to virus. In part because only the interactive fraction of mCAT-1 can be down-modulated, infected murine cells conserve an amino acid transport capability that supports their viability.
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PMID:Modulation of ecotropic murine retroviruses by N-linked glycosylation of the cell surface receptor/amino acid transporter. 879 31

We demonstrated that urinary trypsin inhibitor (UTI) efficiently inhibits soluble and tumor cell-associated plasmin activity and subsequently inhibits tumor cell invasion and metastasis. The effect of UTI on tumor necrosis factor-alpha (TNF)-induced stimulation of urokinase-type plasminogen activator (uPA) in cultured human umbilical vein endothelial cells (HUVEC) and in the promyeloid leukemia U937 cells was studied. uPA antigen was evaluated in the cell lysate and in the conditioned media by enzyme-linked immunosorbent assay, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and Western blot. TNF can promote the production of uPA in HUVEC and in U937 cells. The PKC inhibitors (H7, calphostin C, and staurosporine) inhibited TNF-induced uPA expression and secretion in a dose-dependent manner. Analysis of the expression of cell surface receptor-bound uPA by flow cytometry using uPA-specific MAb indicates that induction of uPA expression by TNF was inhibited when these cells were incubated with UTI. On the other hand, treatment of the cells with UTI alone failed to alter uPA production. UTI also reduced the secretion of uPA in TNF-treated cells. UTI was as effective as PKC inhibitors in inhibiting uPA expression by TNF. Incubation of the cells with UTI, however, had no effect on the ability of PMA to stimulate cell-associated uPA expression. These data suggest that UTI may influence the PKC-dependent protein kinase pathway in uPA expression. The study on intracellular pathways involved in UTI modulation of uPA will enhance our understanding of the role that UTI plays in uPA-mediated cellular invasion.
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PMID:Urinary trypsin inhibitor efficiently inhibits urokinase production in tumor necrosis factor-stimulated cells. 898 Sep 9

The CD28 cell surface receptor provides an important costimulatory signal for T cells necessary for their response to Ag. Early events in CD28 signaling include recruitment and activation of phosphatidylinositol 3-kinase (PI3-kinase) and activation of the protein tyrosine kinases (PTKs), LCK and EMT. Recruitment and activation of PI3-kinase is known to be dependent upon phosphorylation of tyrosine 173 of the CD28 cytoplasmic tail contained within a YMNM motif. By contrast, little is known of which residues of the CD28 tail, including tyrosines, are required for the activation of PTKs. To address this we studied the ability of truncation mutants and tyrosine to phenylalanine substitution mutants of the CD28 cytoplasmic tail to activate LCK and EMT in Jurkat T leukemia cells. Our results indicate that 1) activation of EMT is partially dependent upon tyrosine 173 of the CD28 tail, although it does not require PI3-kinase activation; 2) activation of LCK is independent of CD28 cytoplasmic tail tyrosine residues; and 3) elements sufficient for the activation of both kinases are contained within the first half of the tail. In addition we studied the CD28 tail as a substrate for both PTKs in in vitro kinase assays. We demonstrate that EMT can phosphorylate all four tyrosines of the CD28 tail, in contrast to LCK, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor.
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PMID:Analysis of CD28 cytoplasmic tail tyrosine residues as regulators and substrates for the protein tyrosine kinases, EMT and LCK. 899 71

CD95 (Fas/APO-1) is a cell surface receptor able to trigger apoptosis in a variety of cell types. The expression and function of the CD95 antigen on leukemic blasts from 42 patients with B lineage and 53 patients with T lineage acute lymphoblastic leukemia (ALL) were investigated using immunofluorescence staining and apoptosis assays. The CD95 surface antigen was expressed in most ALL cases, with the T lineage ALL usually showing a higher intensity of surface CD95 expression as compared with the B lineage ALL cells (relative fluorescence intensity, RFI: 4.8 +/- 0.47 vs 2.2 +/- 0.23, respectively, P < 0.01). Functional studies disclosed that upon oligomerization by anti-CD95 monoclonal antibodies the CD95 protein was either not able to initiate apoptosis of leukemic cells (75% of cases) or induced low rates of apoptosis (20% of cases). Only in 5% of cases did the apoptosis rate exceed the 20% level of the CD95-specific apoptosis. Most of the CD95-sensitive cases were found among T lineage ALLs (38% of T lineage vs 10% of B lineage ALLs). Overall, the extent of CD95-induced apoptosis did not correlate with the expression level of CD95. Similarly, no significant correlation between expression level and functionality of CD95 in human leukemia cell lines of B and T cell origin could be observed. Bcl-2 protein has been associated with prolonged cell survival and has been shown to block partially CD95-mediated apoptosis, but for ALL cells no correlation between bcl-2 expression and spontaneous or CD95-mediated apoptosis could be found. The results obtained in this study indicate that, despite constitutive expression of CD95, the ALL cells are mainly resistant to CD95-triggering. More detailed investigations of the molecular mechanisms involved in the intracellular apoptotic signal transduction, such as interactions of the bcl-2 and the other members of the bcl-2 family, and functionality of the interleukin-1beta converting enzyme (ICE) like-proteases, may give new insights into key events responsible for the resistance or sensitivity to the induction of apoptosis in acute leukemia.
Leukemia 1997 Aug
PMID:Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells. 926 77

The cell surface receptor for gibbon ape leukemia virus (Glvr-1) was recently demonstrated to serve normal cellular functions as a sodium-dependent phosphate (NaPi) transporter. This protein belongs to a newly identified phosphate transporter/retrovirus receptor gene family distinct from renal type I and II NaPi transporters. Although inorganic phosphate (Pi) transport is an important function of osteoblasts and of the matrix vesicles produced by these cells in the context of bone matrix calcification, the molecular identity of the NaPi transport system(s) present in this cell type is still unknown. In contrast to Pi uptake mediated by renal NaPi transporters, the activities of both the osteoblastic transport system and Glvr-1 are decreased at alkaline pH, and this observation led us to investigate expression of this transporter in human SaOS-2 osteosarcoma cells. Northern blotting analysis revealed the presence of a 4-kilobase Glvr-1 transcript. The expression of Glvr-1 messenger RNA (mRNA) was increased in response to insulin-like growth factor I (IGF-I). Associated with this effect, a selective, dose- and time-dependent stimulation of NaPi transport was observed. Actinomycin D and cycloheximide abolished the increase in NaPi transport, which thus appeared to be dependent on RNA and protein synthesis. The increase in Glvr-1 mRNA induced by IGF-I was dose dependent and transient, peaking after 4 h (approximately 4-fold increase in response to 10(-7) M IGF-I). It preceded the maximal expression of NaPi transport stimulation (173-235% of control), which was observed after 18-24 h. Induction of Glvr-1 mRNA expression by IGF-I was inhibited by actinomycin D, suggesting that this effect was related to an increase in gene transcription. The stability of Glvr-1 mRNA was not altered by IGF-I, and Glvr-1 mRNA induction did not require the synthesis of new proteins. These data demonstrate for the first time regulated expression of mRNA encoding the type III NaPi transporter Glvr-1 in osteoblast-like cells. They also suggest that this new transporter family may be involved in Pi handling in osteogenic cells and in its regulation by osteotropic factors.
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PMID:Expression of a newly identified phosphate transporter/retrovirus receptor in human SaOS-2 osteoblast-like cells and its regulation by insulin-like growth factor I. 938 2


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