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)

DNA polymerase gamma has been purified over 60 000-fold from HeLa cells which contain no detectable type C viral particles. This purified enzyme shows a specific activity of 25 000 units/mg of protein which is comparable to the known specific activity of homogeneous preparations of human alpha and beta polymerases. The isolated enzyme shows apparent molecular weights ranging from 160 000 to 330 000 according to the method of analysis. The enzyme exhibits optimal activity for copying poly(A) in the presence of 50 mM KPO4 and 130 mM KCl and, under these conditions, copies poly(A) 20 times more rapidly than activated DNA. These assay conditions permit a clear distinction between the gamma-polymerase and DNA polymerase beta which is markedly inhibited by phosphate at this concentration. A comparison of the copying of activated DNA, poly(dA) and poly(A) by DNA polymerases alpha, beta, and gamma under optimal assay conditions for each enzyme is presented. Studies with synthetic and natural nucleic acid templates also show the gamma-polymerase to behave differently that the reverse transcriptases of avian myeloblastosis virus or Rauscher leukemia virus.
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PMID:HeLa cell DNA polymerase gamma: further purification and properties of the enzyme. 97 75

We have compared the relative inhibitory activity of poly (A) with its analogues poly N6-isopentenyl adenylic acid (poly(i6 A)) and poly N6-benzyl adenylic acid (poly(bzl6A)), and of poly (U) with its analogue poly 2'-fluoro-2'-deoxyuridylic acid (poly(dUfl)), against DNA polymerase, alpha, beta and gamma and terminal deoxynucleotidyl transferase from human cells and two oncorna virus DNA polymerases. Although poly (A) and its analogues were equally inhibitory against endogenous RNA-directed DNA polymerases of murine and feline leukemia viruses, the analogues in contrast to poly (A) were strongly inhibitory against all four cellular enzymes. Poly (dUfl), on the other hand, was up to 100-fold more potent than poly (U) against both viral and cellular enzymes. Since poly (U) at 100 mug/ml and poly (dUfl) at 1 mug/ml had no effect on terminal deoxynucleotidyl transferase while inhibiting other enzymes by 80--100 per cent these polymers could be useful in the characterization and assay of terminal deoxynucleotidyl transferase. In addition, the polymers such as poly (igA) and poly (bzl5A) which were strongly inhibitory to all cellular enzymes, could be useful in cancer chemotherapy if taken up preferentially by the malignant calls due to their high pinocytic activity. The results also demonstrate potential for large variation in inhibitory activity of polyribonucleotides as related to their chemical composition.
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PMID:Modified nucleotide polymers as inhibitors of DNA polymerases. 119 5

The high-affinity IgE receptor (Fc epsilon RI), which is expressed on the surface of mast cells and basophils, has a central role in immediate allergic responses. In the rat basophilic leukaemia cell line RBL-2H3, which is a model system for the analysis of Fc epsilon RI-mediated signal transduction, surface engagement of Fc epsilon RI induces histamine release and the tyrosine phosphorylation of several distinct proteins. Although the alpha, beta, and gamma subunits of Fc epsilon RI lack intrinsic tyrosine protein kinase (TPK) activity, a kinase that copurifies with Fc epsilon RI phosphorylates the beta and gamma subunits of the receptor on tyrosine residues. We report here that in RBL-2H3 cells, p56lyn and pp60c-src are activated after Fc epsilon RI crosslinking, and p56lyn coimmunoprecipitates with Fc epsilon RI. In the mouse mast-cell line PT-18, another cell type used to study FC epsilon RI-mediated signalling, tyrosine phosphorylation of proteins is also an immediate consequence of receptor crosslinking. Notably, the only detectable src protein-related TPK in PT-18 cells is p62c-yes, and it is this TPK that is activated on Fc epsilon RI engagement and coimmunoprecipitates with the receptor. Therefore, it seems that different src protein-related TPKs can associate with the same receptor and become activated after receptor engagement.
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PMID:Engagement of the high-affinity IgE receptor activates src protein-related tyrosine kinases. 137 May 75

We have shown previously that infection of mononuclear cells derived from neonatal cord (CBMC) or adult peripheral (PBMC) blood with HTLV-1 can be controlled in vitro by treatment with interferon (IFN) alpha, beta or gamma. The activity of IFNs was mainly related to the induction of an active antiviral competence in host's immune effector cells. The antiviral activity of IFN-boosted CBMC could be ascribed both to a positive regulation of cell-mediated immunity and to inhibition of viral infection. Data described herein provide further information on the mechanisms of the antiviral activity of IFNs and compare the activity of each type of IFN with the association of alpha + beta, alpha + gamma and beta + gamma IFNs, at a concentration of 100 or 1000 IU/ml. When added at the onset of the co-culture of CBMC with lethally irradiated, virus-donor MT-2 cells, IFNs could protect host CBMC by inhibiting HTLV-1 infection in terms of reduced proviral integration and a lower percentage of virus-positive cells, until 4 weeks of culture. Infection of CBMC was inhibited at a comparable extent by either individual or combined IFN treatments. However, a clearcut inhibition of HTLV-I transcription was found only when alpha 100 + beta 1000 IU/ml and especially alpha 1000 + gamma 100 IU/ml combined treatments were tested. When the chronically infected, virus-producing MT-2 cells were treated with IFNs, a remarkable inhibition of HTLV-I transcription was found only after multiple treatments. However, MT-2 cells became resistant to the antiviral activity of IFN gamma, but not to that of IFN alpha or beta. These data provide further information on the control of HTLV-I replication mediated by IFNs at different steps of the viral life cycle, being therefore relevant to the clinical use of combined IFNs in the treatment of acute infection. Moreover, IFNs could be used to prevent the establishment of a persistent infection, which is a prerequisite for developing adult T-cell leukemia (ATL) and/or virus-associated myelopathy.
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PMID:Antiviral activity of individual versus combined treatments with interferon alpha, beta and gamma on early infection with HTLV-I in vitro. 142 62

When aggregated, cell surface proteins become resistant to solubilization by detergents, presumably because of aggregation-induced or -stabilized interactions between the membrane protein and the cytoskeleton or plasma membrane skeleton. We genetically engineered variants of the tetrameric high-affinity receptor for IgE (Fc epsilon RI) to identify a site on its alpha, beta, or gamma chains that mediates such putative interactions. Using flow cytofluorometry, we studied rat basophilic leukemia cells, transiently transfected COS cells, and stably transfected P815 cells bearing wild-type and mutated receptors. We observed that (i) solubilization was markedly dependent on the degree of aggregation, the extent varying somewhat with the cell type and, particularly at lower levels of aggregation, with the time after addition of detergent; (ii) truncation of no single cytoplasmic domain of the alpha, beta, or gamma chains ablated the insolubilization effect; and (iii) incomplete receptors were also efficiently insolubilized by aggregation. Thus receptors consisting only of alpha and gamma chains, a "receptor" consisting of only the ectodomain of the alpha chain attached to the plasma membrane by a glycosyl-phosphatidyl inositol anchor, and "receptors" consisting only of minimally modified gamma chains were resistant to solubilization after aggregation. We conclude that no unique subunit or domain of Fc epsilon RI mediates the insolubilization phenomenon. Our results support a model in which the bridging of membrane proteins leads to their becoming nonspecifically enmeshed in a network of membrane skeletal proteins on either the outside and/or the inside of the membrane so that dissolution of the lipid bilayer becomes irrelevant.
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PMID:Interaction of aggregated native and mutant IgE receptors with the cellular skeleton. 153 Aug 86

The effects of recombinant human interferons alpha, beta and gamma (IFN) on the antiproliferative activity of cytarabine in K562 human myeloid leukaemia clonogenic cells were studied in an agar capillary microassay. The addition of IFN-alpha did not affect the antiproliferative activity of cytarabine in K562 cultures treated with low concentrations of cytarabine (10-50 nM), whereas in those treated with high concentrations (100-150 nM) IFN alpha increased the IC50 of cytarabine on day 5 from 102 nM to 214 nM, i.e., cytarabine combined with IFN alpha was about two-fold less potent than cytarabine alone. Similarly, low concentrations of IFN beta and IFN gamma did not affect the antiproliferative activity of cytarabine on K562 colonies, but high concentrations of these two interferons: 4 x 10(3) U/ml and 10(4) U/ml respectively, increased the IC50 of cytarabine on day 5 to 304 nM and to 316 nM respectively, i.e. cytarabine combined with IFN beta or IFN gamma was about threefold less potent than cytarabine alone. The evaluation of the present negative interactions of interferons with cytarabine is warranted in fresh cells from myeloid leukaemia patients in primary culture.
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PMID:Recombinant human interferons alpha, beta and gamma reduce the antiproliferative action of cytarabine in K562 human myeloid leukaemia clonogenic cells. 158 63

The mechanisms by which non-oncogene bearing, slowly transforming T-cell-tropic retroviruses induce leukemia is not well understood. Viruses such as the murine radiation leukemia virus (RadLV) induce oncogenic transformation of T-cells in the thymus only in vivo and after a long latency. The capacity of RadLV to induce proliferation of lymphoid cells in vitro has been analysed here as a first attempt at mapping oncogenic transformation. Autonomously replicating cell lines have been isolated following exposure of splenic lymphocytes to two different isolates of RadLV, following in vitro culture in the presence of T-cell growth factors. Cells of similar precursor lymphoid morphology and phenotype have been isolated and cloned from cultures established from different animals. These cell lines all grow independently of exogenous growth factors in vitro, but are not tumorigenic in mice. Exposure to RadLV under the culture conditions provided has allowed integration of a new retroviral genome into each cell line, but no active replication of virus has been detected in any of the cell lines analysed. A common cell type resembling a lymphoid precursor has been induced to proliferate. These cell lines express cell surface markers attesting to their bone marrow origin, such as CD44 (Pgp-1), Gr-1, B220 and NK1.1, but they do not show the characteristics of T cells which have undergone differentiation within the thymus. They do not express the Thy-1 marker, nor show rearrangement involving any of the T-cell receptor (TCR) alpha, beta gamma or sigma genes. These cells bind several antibodies specific for the CD3-epsilon and TCR-alpha beta structures, and there appears to be aberrant expression of TCR proteins in cells bearing fully rearranged TCR genes. Precursor lymphoid cells and not mature T-cells in spleen, appear to be appropriate targets for RadLV-induced proliferation/immortalisation in vitro. Oncogenic transformation induced by RadLV in vivo may occur within precursor lymphoid cells and must be a complex process dependent on both the differentiation events which occur within the thymus, as well as the thymic environment of stromal cells.
Leukemia 1992 Apr
PMID:Unique lymphoid cell subset target to infection and proliferation induced in vitro by a murine leukemia virus. 158 90

Retinoic acid receptor (RAR) and thyroid hormone receptor (T3R) are thought to bind as dimers to a T3 responsive element (T3REpal) comprised of inverted repeats of the half-site motif GGTCA. However, a RA responsive element (beta RARE) was previously identified in the promoter of the RAR beta 2 gene which contains two direct repeats of the motif GTTCA spaced by a six nucleotide gap. We now demonstrate the ability of RAR alpha, beta and gamma to bind to and transactivate through this element and that the two direct repeats comprise the beta RARE. Surprisingly, the GTTCA motifs rearranged to form a palindrome do not confer RA responsiveness to a heterologous promoter. Furthermore, no significant level of transactivation is detected by ligand-activated RAR through the Moloney murine leukaemia virus T3RE, which comprises two direct repeats of the sequence GGTCA/C spaced by a five nucleotide gap. Similarly, T3R does not induce gene expression through the beta RARE. This study establishes the preference of T3R to transactivate through direct repeats spaced by a five nucleotide gap as opposed to a six nucleotide gap. In contrast, RAR appears to be more flexible with respect to spacing requirements between repeats, although higher levels of transactivation are obtained through direct repeats spaced by a six nucleotide gap. Interestingly, although some elements mediate either RA or T3 induction, changing a single nucleotide in the MoMLV T3RE with a five nucleotide spacing creates a promiscuous RA/T3 responsive element.
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PMID:Functional characterization of a natural retinoic acid responsive element. 165 95

Interferons are a family of proteins shown to be effective in the treatment of viral (condylomata, acuminata) and neoplastic (hairy cell leukaemia and AIDS-related Kaposi's sarcoma) diseases. To date, the clinical utility of the interferons has been hampered by an incomplete understanding of their mechanism of action. However, there is supporting evidence that the route of administration, i.e. the pharmacokinetic behaviour, is an important treatment variable. The pharmacokinetics of interferons have been fairly well described. The decline in serum concentrations of interferon is rapid after intravenous administration. The volume of distribution approximates 20 to 60% of bodyweight. Work in animals suggests that the catabolism of interferons falls within the natural handling of proteins. Clearance values vary (4.8 to 48 L/h) across the family of interferons and probably reflect the natural internal digestion and turnover of these proteins. Terminal elimination half-lives range from 4 to 16 hours, 1 to 2 hours and 25 to 35 minutes for alpha, beta and gamma, respectively. Intramuscular and subcutaneous administration of interferons alpha and beta results in protracted but fairly good absorption: greater than 80% for interferon-alpha and 30 to 70% for interferon-gamma. Interferon therapy is associated with adverse events which are usually mild and reversible. Temporal relationships exist between the degree and duration of adverse effects and the route of administration. Attempts to relate inducible biochemical markers, such as 2',5'-oligoadenylate synthetase activity, to dose or concentration have met with some success although alterations in these markers have not been shown to relate to clinical response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics of interferons. 170 93

The interferons (IFN) are one of the body's natural defensive responses to such foreign components as microbes, tumors, and antigens. The IFN response begins with the production of the IFN proteins (alpha, beta, and gamma), which then induce the antiviral, antimicrobial, antitumor, and immunomodulatory actions of IFN. Recent advances have led to Food and Drug Administration approval of five clinical indications for IFN. Interferon alfa is approved for hairy-cell leukemia, condyloma acuminatum, Kaposi's sarcoma in the acquired immunodeficiency syndrome, and non-A, non-B (type C) viral hepatitis. Interferon gamma has properties distinctive from those of IFNs alpha and beta and is approved as an immunomodulatory treatment for chronic granulomatous disease. Promising clinical results with IFNs have also been reported for basal cell carcinoma, chronic myelogenous leukemia, cutaneous squamous cell carcinoma, early human immunodeficiency virus infection, hepatitis B, and laryngeal papillomatosis. Future clinical uses of IFNs may emphasize combination therapy with other cytokines, chemotherapy, radiation, surgery, hyperthermia, or hormones.
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PMID:The interferons. Mechanisms of action and clinical applications. 137 Mar 33


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