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)

There have been an increasing number of reports describing a pivotal role for phosphorylation in cellular responses for cell differentiation and proliferation. We examined an immunocytochemical expression of protein kinase C(PKC) isozymes (type I, II, and III) in 22 leukemia-lymphoma cell lines. Of these cell lines, 21 expressed type II PKC and 17 showed the co-expression of both types II and III PKC in varying degree. The cell line without PKC activity showed far less [3H]-TdR uptake and no heterotransplantation in nude mice. Types II and III PKC appear to relate to cell proliferation in certain leukemia-lymphoma cell lines.
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PMID:Protein kinase C isozyme expression in human leukemia-lymphoma cell lines--an immunocytochemical study. 129 30

Protein kinase C (PKC) regulates many cellular processes. In view of its possible relevance to the drug resistance, the levels of PKC activity were assessed in human leukemia cell lines with reference to the sensitivity to antineoplastic agents. K562/ADM exhibited approximately 2-fold higher levels of PKC activity as compared with the parental K562. After a 1-hr preincubation with Adriamycin (ADM) (0.5, 1, 10 microM), PKC activity in K562 tended to increase dose-dependently, while no substantial alteration was found in K562/ADM. Cisplatin (CDDP) or etoposide was of no effect. The activity in THP-1/E was slightly lower than THP-1, and the basal level stayed unchanged with any one of the above drugs. These results suggest that in K562 increase in PKC activity with ADM may play a role in the process of acquisition of resistance.
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PMID:Protein kinase C activity in human leukemia cell lines with reference to sensitivity to antineoplastic agents. 130 25

Membrane interactions of tetradecapeptide toxin mastoparan (MP) and analogues (MP-3, MP-X and polistes MP), as indicated by inhibition of various enzymatic and cellular activities, were investigated. MP-3 was found to be the least active in inhibiting protein kinase C (PKC; activated by phosphatidylserine vesicles, synaptosomal membranes or phorbol ester), synaptosomal membrane Na,K-ATPase and proliferation and viability of leukemia HL60 cells. MP-3, however, was as active as others in inhibiting PKC activated by arachidonate monomers and phorbol ester binding. The unique properties of MP-3, the [des-Ile1-Asn2]-analogue of MP, might be related to its low functional amphiphilicity compared to others and useful in further delineating biological activities associated with or regulated by membranes.
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PMID:Membrane interactions of mastoparan analogues related to their differential effects on protein kinase C, Na, K-ATPase and HL60 cells. 132 33

Naturally occurring recombinant murine leukemia viruses (MuLVs), termed mink cell focus-inducing (MCF) viruses, are the proximal leukemogens in spontaneous thymic lymphomas of AKR mice. The mechanism by which these viruses transform lymphocytes is not clear. Previous studies have implicated either integrational activation of proto-oncogenes, chronic autocrine immune stimulation, and/or autocrine stimulation of growth factor receptors (e.g., interleukin 2 receptors) via binding of the viral env glycoprotein (gp70) to these receptors. Any one of these events could also involve activation of second messenger signaling pathways in the cell. We examined whether infection with oncogenic AKR-247 MCF MuLV induced transmembrane signaling cascades in thymocytes of AKR mice. Cyclic AMP levels were not changed, but there was enhanced turnover of phosphatidylinositol phosphates, with concomitant increases in diacyglycerol and inositol 1,4,5-triphosphate. Thus, phospholipase C activity was increased. Protein kinase C activity was also elevated in comparison to that in uninfected thymocytes. The above events occurred in parallel with MCF expression in the thymus and were chronically maintained thereafter. No changes in phospholipid turnover occurred in an organ which did not replicate the MCF virus (spleen) or in thymocytes of AKR mice infected with a thymotropic, nononcogenic MCF virus (AKV-1-C36). Therefore, only the oncogenic MCF virus induced phosphatidylinositol signal transduction. Flow cytometric comparison of cell surface gp70 revealed that AKR-247 MCF virus-infected thymocytes expressed more MCF virus gp70 than did thymocytes from AKV-1-C36 MCF virus-infected mice, suggesting that certain threshold quantities of MCF virus env glycoproteins may be involved in this signaling. This type of signal transduction is not induced by stimulation of the interleukin 2 receptor but is involved in certain oncogene systems (e.g., ras and fms). Its chronic induction by oncogenic MCF MuLV may thus initiate thymocyte transformation.
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PMID:Oncogenicity of AKR mink cell focus-inducing murine leukemia virus correlates with induction of chronic phosphatidylinositol signal transduction. 132 63

The mAb AA4 binds to novel derivatives of the ganglioside Gd1b on rat basophilic leukemia (RBL-2H3) cells. Some of the gangliosides are located close to the high affinity IgE receptor (Fc epsilon RI), and binding of mAb AA4 inhibits Fc epsilon RI-mediated histamine release. In the present study, mAb AA4 was found to bind exclusively to mast cells in all rat tissues examined. In vitro, within 1 min of mAb AA4 binding, the cells underwent striking morphologic changes. They lost their normal spindle shaped appearance, increased their ruffling, and spread over the surface of the culture dish. These changes were accompanied by a redistribution of the cytoskeletal elements, actin, tubulin, and vimentin, but only the actin was associated with the membrane ruffles. Binding of mAb AA4 also induces a rise in intracellular calcium, stimulates phosphatidyl inositol breakdown, and activates PKC. However, the extent of these changes was less than that observed when the cells were stimulated with antigen or antibody directed against the Fc epsilon RI. None of these changes associated with mAb AA4 binding were seen when the cells were exposed to nonspecific IgG, IgE, or four other anti-cell surface antibodies, nor were the changes induced by binding mAb AA4 at 4 degrees C or in the absence of extracellular calcium. Although mAb AA4 does not stimulate histamine release, it enhances the effect of the calcium ionophore A23187 mediated release. The morphological and biochemical effects produced by mAb AA4 are similar to those seen following activation of the cell through the IgE receptor. Therefore, the surface gangliosides which bind mAb AA4 may function in modulating secretory events.
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PMID:Binding of monoclonal antibody AA4 to gangliosides on rat basophilic leukemia cells produces changes similar to those seen with Fc epsilon receptor activation. 137 Apr 98

Protein kinase C (PKC) has been shown to be involved in the mitogenic response and in oncogenic cell transformation in many experimental models. We analyzed the expression of PKC in both highly purified leukemic T cells freshly isolated from adult T-cell leukemia (ATL) patients and control T lymphocytes obtained from healthy volunteers. PKC activity was decreased in the ATL cells as compared with the control T cells. Cytosolic PKC activity in the ATL cells was remarkably decreased, whereas particulate membrane PKC activity was similar to the control level. The percentage of PKC activity in the particulate fraction was 34% in the ATL cells and 19% in the control cells. Regarding the altered subcellular localization of PKC activity, phorbol ester-induced translocation of cytosolic PKC was inhibited in some ATL cases. Similarly to the decrease in PKC activity, there was a decrease in the expression of the major PKC isozymes II(beta) and III(alpha) in ATL cells. These results suggest impaired regulation of PKC expression in ATL as well as in many experimental cancers.
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PMID:Altered expression of protein kinase C in adult T-cell leukemia cells. 142 Nov 75

NF kappa B is a potent mediator of specific gene expression in human monocytes and has been shown to play a role in transcription of the HIV-1 genome in promonocytic leukemias. There is little information available on the response of NF kappa B to cytokines in normal human monocytes. We have used a 32P-labeled oligonucleotide derived from human immunodeficiency virus (HIV-1) long terminal repeat, which contains a tandem repeat of the NF kappa B binding sequence, as a probe in a gel retardation assay to study this transcription factor. Using this assay, we have detected NF kappa B in extracts of nuclei from normal human monocytes. Treatment of normal monocytes with 12-0-tetradecanoyl phorbol-13-acetate (TPA) for 4-24 h caused the complete disappearance of NF kappa B from nuclear extracts of monocytes. A similar result was obtained with the mature monocytic leukemia cell line THP-1. The constitutive transcription factor SP1 was unaffected by addition of TPA. The disappearance of NF kappa B from the nucleus was concentration dependent between 10 and 50 ng/ml of phorbol ester. In THP-1 cells, TPA also induced a new, faster-migrating NF kappa B species not induced in monocytes. Protein kinase C inhibitor staurosporine, but not cyclic nucleotide-dependent protein kinase inhibitor HA-1004, also dramatically reduced constitutive levels of nuclear NF kappa B. Finally, TPA addition to monocytes infected with HIV-1 inhibited HIV-1 replication, as determined by reverse transcriptase assays, in a concentration-dependent manner. These results are in striking contrast to the increase in nuclear NF kappa B and HIV-1 replication induced by phorbol esters in promonocytic leukemia cells U937 and HL-60, and emphasize the importance of studying cytokine regulation of HIV-1 in normal monocytes.
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PMID:Phorbol ester reduces constitutive nuclear NF kappa B and inhibits HIV-1 production in mature human monocytic cells. 146 36

Protein kinase C (PKC) isoforms are key mediators in hormone, growth factor, and neurotransmitter triggered pathways of cell activation (Nishizuka: Science 233:305-312, 1986; Nature 334:661-665, 1988). Stimulation of kinase activity by diacylglycerol and calcium often leads to translocation of PKC from the cytosol to a particulate fraction (Kraft and Anderson: Nature 301:621-623, 1983). The beta isoform of PKC is translocated and degraded much more rapidly than the alpha isoform in phorbolester-stimulated rat basophilic leukemia (RBL) cells (Huang et al.: J. Biol. Chem. 264:4238-4243, 1989). We report here immunofluorescence evidence that the distributions of PKC alpha and beta are strikingly different in antigen-activated RBL cells. PKC beta associates with perinuclear filaments and filaments that extend from the perinuclear area to the cell periphery whereas PKC alpha concentrates in regions of the cell periphery. This distribution of PKC beta is distinctly different from that of actin filaments and microtubules as determined by phalloidin staining and by anti-tubulin antibody labeling. In contrast, the staining patterns obtained with antibodies to PKC beta and to the intermediate filament protein vimentin are almost identical, indicating that PKC beta associates with vimentin filaments. These bundles of 100 A filaments may provide docking sites for interactions of PKC beta with its substrates and thus confer specificity to the actions of this isoform.
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PMID:Association of the beta isoform of protein kinase C with vimentin filaments. 151 48

Novel derivatives of K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl- 8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibe nzo[a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i.p.-i.p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca(2+)- and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparently exhibited DNA scission both dose- and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases.
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PMID:Antitumor effect of KT6124, a novel derivative of protein kinase inhibitor K-252a, and its mechanism of action. 153 71

smg p21A and -B (smg p21s) are ras p21-like small GTP-binding proteins (G proteins) with the same putative effector domain as ras p21s. Both smg p21A mRNA and smg p21B mRNA were detected in CMK, a human megakaryocytic leukemia cell line, and their levels were markedly elevated by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which caused the differentiation of this cell line into more mature megakaryocytes. The smg p21 protein molecules also increased during the TPA-induced differentiation of CMK cells. The mRNA level of glycoprotein IIb (GPIIb), a typical marker of the megakaryocytes, was increased by this treatment, but the time course of the increase in the smg p21 mRNA levels as more rapid than that of the increase in the GPIIb mRNA level. Ha-ras p21 mRNA was undetectable, but both Ki- and N-ras p21 mRNAs were detected in CMK cells and their levels were also increased during TPA-induced differentiation of CMK cells, although to a lesser extent than those of smg p21 mRNAs. Protein kinase C inhibitors inhibited the basal and TPA-induced smg p21A mRNA level, but cyclic AMP-elevating prostaglandin E1 or Ca(2+)-mobilizing ionomycin did not inhibit them. Cycloheximide enhanced the basal and TPA-induced smg p21A mRNA levels. Actinomycin D blocked the TPA-induced smg p21A mRNA levels, but showed no detectable effect on the elevated smg p21A mRNA level which was induced by pretreatment with TPA. A dramatic increase in the smg p21 mRNA levels was also observed in other leukemia cell lines during TPA-induced differentiation. These results suggest that TPA stimulated expression of the smg p21A gene, presumably through the action of protein kinase C at the transcriptional level rather than at the post-transcriptional level, in hematopoietic leukemia cells.
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PMID:Induction of smg p21/rap1A p21/krev-1 p21 gene expression during phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line. 154 53


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