UMLS:C0023418 - FACTA Search

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

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

Short-term stimulation (up to 16 hours) of interleukin-3 (IL-3)-dependent mouse bone marrow-derived mast cells, Abelson transformed mouse liver-derived mast cells, or rat basophilic leukemia cells by either IgE-Ag or calcium ionophore A23187 resulted in inhibition of their proliferation as measured by 3H-thymidine incorporation and MTT (tetrazolium) assays, and in accumulation of the mRNAs of c-fos, c-jun, junB and slightly of junD proto-oncogenes. The involvement of protein kinase C (PKC) in these responses was investigated by using several approaches of enzyme activity regulation. Direct activation of the PKC was achieved by short-term exposure of the cells to the PKC-specific activator phorbol 12-myristate-13-acetate (PMA). Inhibition of PKC activity was obtained by either prolonged treatment of the cells with PMA or by exposure of the cells to the PKC inhibitors H-7 and staurosporine. The results showed the following: (1) Short-term exposure of mast cells to PMA was sufficient to induce inhibition of proliferation. (2) An increase in PKC activity was associated with a decrease in the proliferation of IgE-dinitrophenol (DNP) or calcium ionophore A23187-stimulated cells. (3) A direct correlation was found between the increase in PKC activity and the increase in the level of the mRNAs of the jun proto-oncogenes in cells activated by both stimuli mentioned. (4) While an increase in PKC activity was associated with the upregulation of the level of c-fos mRNA during calcium ionophore A23187 stimulation, it showed the opposite effect on the expression of the mRNA of this proto-oncogene when the cells were triggered by IgE-DNP. Therefore, we concluded that PKC plays various roles in the expression of the mRNA of c-fos in activated mast cells depending on the stimulus involved. In addition, the expression of the mRNA of c-jun and junB proto-onogenes is not coordinately regulated with that of c-fos during immunologic stimulation. This discordancy, which is associated with the increase in PKC activity in mast cells, may play a role in the regulation of the transcription of AP-1-responsive genes, and therefore could be associated with the regulation of proliferation of these cells.
...
PMID:Protein kinase C regulates proliferation of mast cells and the expression of the mRNAs of fos and jun proto-oncogenes during activation by IgE-Ag or calcium ionophore A23187. 193 49

Phorbol myristate acetate (PMA) but not its inactive analogue phorbol didecanoate modulated the release of [3H] serotonin by rat basophilic leukemia (RBL) cells stimulated by antigen-IgE complexes. Concanavalin A or the calcium ionophore ionomycin, suggesting that protein kinase C (PKC) was involved in the exocytosis process. The PKC inhibitor sphingosine markedly inhibited release. When the PKC content of RBL cells was diminished by a prior 24 h-exposure (long-term PMA-treated cells) to 50 or 100 ng/ml PMA, the release induced by the three secretagogues was also strongly inhibited. Since cell activation by PMA in different cell systems is accompanied by PKC translocation from cytosol to membrane, we studied the location of PKC in resting cells and its translocation by a 5 min-exposure to 100 ng/ml PMA. PKC was cytosolic in long-term PMA-treated and control RBL cells and its translocation occurred regardless of the total PKC cell content, showing a possible correlation between the level of functional PKC (susceptible to be translocated) and exocytosis. Taken together, these data suggest that PKC is involved in the controlling of exocytosis by different secretagogues.
...
PMID:Rat basophilic leukemia cells: protein kinase C and secretion. 193 87

Previous studies have shown that treatment of human myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation and expression of the c-jun and c-fos early response genes. The present work demonstrates that the glucocorticoid dexamethasone inhibits TPA-induced increases in c-jun and c-fos mRNA levels in U-937 leukemia cells. These findings were associated with a block in appearance of the monocytic phenotype, including inhibition of TPA-induced increases in lamin A, lamin C, and vimentin transcripts. Other studies have demonstrated that TPA-induced monocytic differentiation and expression of the c-jun and c-fos genes in myeloid leukemia cells are regulated by protein kinase C (PKC). The finding that dexamethasone has no effect on TPA-induced activation of PKC suggests that this glucocorticoid inhibits signals downstream or parallel to this enzyme. Nuclear run-on assays demonstrate that: (1) induction of c-jun and c-fos expression by TPA is regulated by transcriptional mechanisms, (2) TPA-induced expression of c-jun and c-fos does not require protein synthesis, and (3) TPA-induced expression of both genes is inhibited at the transcriptional level by dexamethasone. To further define the effects of dexamethasone at the molecular level, we prepared a series of deleted c-jun promoter fragments linked to the chloramphenicol acetyltransferase (CAT) gene. Increases in CAT activity during transient expression of these constructs in TPA-treated U-937 cells could be assigned to the region (-97 to -20) of the promoter that contains the AP-1 binding site. This induction of CAT activity was sensitive to dexamethasone. These findings suggest that dexamethasone down-regulates TPA-induced transcription of the c-jun gene during monocytic differentiation by inhibiting activation of the AP-1 site.
...
PMID:Inhibition of phorbol ester-induced monocytic differentiation by dexamethasone is associated with down-regulation of c-fos and c-jun (AP-1). 193 41

Evidence is presented that human monocytes and acute myeloblastic leukemic (AML) cells contain both high and low affinity binding sites for interleukin-4 (IL-4). On monocytes 183 +/- 132 high affinity binding sites per cell with a Kd of 60 +/- 29 pM and 1500 +/- 600 low affinity receptors with a Kd of 2.3 +/- 0.4 nM (X +/- S.D., n = 6) could be demonstrated. On AML cells (n = 11) a comparable number and binding affinity of IL-4 receptors were observed (77 +/- 36 high affinity receptors with Kd 72 +/- 31 pM and 2400 +/- 1000 low affinity receptors with Kd of 2.2 +/- 0.7 nM). In addition, no cross-competition was shown between radiolabeled IL-4 and IL-1-alpha, IL-3, IL-6, IL-7, G-CSF, and GM-CSF. Both types of receptors on monocytes as well as on leukemic blasts could be down-modulated in a similar fashion by IL-4 and activators of protein kinase C (PKC), but not by the calcium ionophore A23187. The down-modulation by PKC activators was caused by an increased internalization, degradation and release of radiolabeled IL-4 in the medium. Finally, the functionality of the IL-4 receptors were tested on AML cells with a 3H-thymidine proliferation assay. In 8/11 cases IL-4 affected AML proliferation. These data demonstrate two different binding sites for IL-4 on normal and leukemic cells, which can be modulated by external activation signals in an analogous way.
Leukemia 1991 Sep
PMID:Expression and regulation of IL-4 receptors on human monocytes and acute myeloblastic leukemic cells. 194 30

Our previous immunocytochemical study showed that Ca2+ ionophore-induced translocation of protein kinase C (PKC) in human megakaryoblastic leukemia cells (MEG-01) was potentiated by a synthetic diacylglycerol (T. Ito, T. Tanaka, T. Yoshida, K. Onoda, H. Ohta, M. Hagiwara, Y. Itoh, M. Ogura, H. Saito, and H. Hidaka, 1988, J. Cell Biol. 107, 929). In the present study, we analyzed the roles of the intracellular Ca2+ levels ([Ca2+]i) and diacylglycerol (DG) levels in thrombin-induced translocation of PKC using MEG-01 cells. When the cells were treated with thrombin (0.5 U/ml), PKC was translocated from the cytosol to the plasma membrane after 15 s, and the maximal membrane association was observed after 90 s. The [Ca2+]i of the cells rapidly increased (15 s) and reached a maximum level at 60 s which was sustained for a total of 600 s after thrombin addition. The increase in DG was biphasic with the first phase occurring in the first 15 s and the increase during the second phase lasting less than 600 s. The experiments without extracellular Ca2+ indicated that Ca2+ efflux accompanied by DG in the first phase was sufficient to initiate the membrane association of the PKC and that the large Ca2+ influx enhanced the binding. PKC returned to the cytosol within 600 s despite high levels of both [Ca2+]i and DG. We found that a relatively selective PKC inhibitor, H-7, enhanced thrombin-induced translocation of PKC without modulating [Ca2+]i or DG levels. These results indicate that certain protein phosphorylation events, potentially those mediated by PKC, may be responsible for, at least in part, inhibiting membrane association and further activation of the enzyme.
...
PMID:Thrombin-induced translocation of protein kinase C in human megakaryoblastic leukemia cells (MEG-01). 195 35

Human promyelocytic leukaemia (HL-60) cells were employed to study the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme in controlling prostaglandin inactivation. Phorbol 12-myristate 13-acetate (PMA) stimulated 15-PGDH activity in a time- and concentration-dependent manner. Dimethyl sulphoxide (DMSO) also stimulated the enzyme activity, although a much delayed stimulation was observed. Western blot studies indicated that PMA increased significantly a 28 kDa immunoreactive protein characteristic of 15-PGDH. L-[35S]Methionine labelling of the PMA-treated cells showed a similar enhancement over the control cells. These studies indicate that PMA induced synthesis of 15-PGDH. Stimulation of 15-PGDH activity by PMA or DMSO appears to be mediated by protein kinase C activation, since an inactive analogue of PMA failed to induce the effect, and both staurosporine and H-7 blocked the stimulation. Stimulation by PMA was optimal at 10 nM and less effective at higher concentrations. Western blot studies indicated that a similar, if not greater, amount of enzyme protein was induced at high concentrations of PMA, suggesting that enzyme inactivation might be occurring. Possible enzyme inactivation by protein kinase C activation was further examined by incubating DMSO-treated cells with a high concentration of PMA (50 nM). Time-dependent inactivation of 15-PGDH within the first 1 h was observed and this inactivation was partially blocked by staurosporine and H-7. Pulse-chase experiments indicated that 15-PGDH had a rapid turnover rate (t 1/2 = 47 min), and PMA shortened the half-life of the enzyme (t 1/2 = 33 min), suggesting that PMA might have an additional effect on 15-PGDH degradation. The rapid turnover of 15-PGDH indicates that the enzyme activity depends on continued enzyme synthesis, and this could be susceptible to hormone and drug control mechanisms.
...
PMID:Stimulation of synthesis de novo of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase in human promyelocytic leukaemia (HL-60) cells by phorbol ester. 195 49

The aim of this study was to clarify the relationship between the stimulatory effects of protein kinase C activators, including phorbol 12-myristate 13-acetate (PMA) and bryostatin, on the hydrolysis of phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) and on PtdCho synthesis. The cell lines used were selected because of their differential responses to protein kinase C activators and included rat-1 fibroblasts, untransformed and A-raf-transformed NIH 3T3 fibroblasts and human HL60 leukaemia cells. Exposure of rat-1 and NIH 3T3 fibroblasts to 100 nM-PMA stimulated phospholipase D-mediated hydrolysis of phospholipids about 2- and 6-fold respectively. In contrast, 100 nM-PMA had similar (2.5-3.0-fold) stimulatory effects on PtdCho synthesis in these cell lines. In the untransformed NIH 3T3 cells, both PMA and bryostatin stimulated both phospholipid hydrolysis and PtdCho synthesis, with 100 nM-bryostatin being somewhat less potent than 100 nM-TPA. In contrast, in A-raf-transformed NIH 3T3 cells or in HL60 cells, only TPA, but not bryostatin, stimulated PtdCho synthesis. In these transformed cells, bryostatin had 3-fold, or higher, stimulatory effects on phospholipid hydrolysis. Addition of ionomycin, a Ca2(+)-elevating agent, partially restored the stimulatory effect of bryostatin on PtdCho synthesis, but it failed to modify the effect of bryostatin on phospholipid hydrolysis. These data indicate that increased phospholipid hydrolysis is not necessarily associated with increased PtdCho synthesis.
...
PMID:Stimulation of phosphatidylcholine synthesis by activators of protein kinase C is dissociable from increased phospholipid hydrolysis. 198 80

The Na(+)-dependent transport and facilitated diffusion of uridine were measured after differentiation of HL-60 leukaemia cells along the monocytic pathway by phorbol 12-myristate 13-acetate (PMA). PMA (200 ng/ml) caused a marked increase in Na(+)-dependent uridine transport within 48 h of exposure that was attributable to an increase in transport affinity (apparent Km values of 1.15 +/- 0.22 and 44 +/- 4.4 microM for PMA-induced and uninduced cells respectively), with no change in Vmax. (0.15 +/- 0.02 and 0.13 +/- 0.01 pmol/s per microliter of cell water for PMA-induced and uninduced cells respectively). A corresponding rapid decrease in both the rate of facilitated diffusion and the formation of uracil nucleotides occurred in PMA-induced cells. As a consequence of these changes, intracellular pools of uridine 3-4-fold greater than those in the medium were generated. A similar increase in Na(+)-dependent transport of adenosine, inosine, guanosine, thymidine and cytidine (Km values of 1-4 microM) was observed. The effects of PMA on the activation of the Na(+)-dependent uridine transporter were inhibited by staurosporine, suggesting the involvement of protein kinase C. The findings indicate that a change in the balance of the cellular mechanisms employed for nucleoside transport occurs during the monocytic differentiation of HL-60 leukaemia cells.
...
PMID:Induction of the differentiation of HL-60 cells by phorbol 12-myristate 13-acetate activates a Na(+)-dependent uridine-transport system. Involvement of protein kinase C. 200 Dec 55

The role of protein kinase C in phospholipase A2 (PLA2) activation in rat basophilic leukemia cells (RBL-2H3) and macrophages was investigated. 12-O-Tetradecanoyl phorbol 13-acetate (TPA) doubled ionomycin-induced PLA2 activity, assessed by [3H]arachidonate release. Protein kinase C inhibitors, staurosporine and K252a (100 nM) or H-7 (15 micrograms/ml) inhibited ionomycin-stimulation of PLA2 activity by 62, 75 and 80%, respectively. Down-regulation of protein kinase C by prolonged treatment with TPA inhibited Ca2(+)-ionophore A23187 or antigen-stimulation of [3H]arachidonate release by 80%. We examined whether the inhibitory effect of dexamethasone (DEX) on PLA2 activity is related to modulation of protein kinase C activity. The 50% inhibition by DEX of ionomycin elevation of [3H]arachidonate release was almost overcome by addition of TPA. The Ca2+ ionophore and antigen-induced increase in [3H]TPA binding to intact RBL cells was not impaired by DEX. However, DEX markedly reduced phosphorylation of several proteins. 1-Oleoyl-2-acetyl-glycerol (OAG) had a sustained stimulatory effect on PLA2 activity in isolated plasma membranes derived from treated bone-marrow intact mouse macrophages, while both DEX and staurosporine reduced elevated PLA2 activity by 68 and 84%, respectively. The results support an essential role for protein kinase C in regulation of PLA2 activity.
...
PMID:Arachidonic acid release by basophilic leukemia cells and macrophages stimulated by Ca2+ ionophores, antigen and diacylglycerol: essential role for protein kinase C and prevention by glucocorticosteroids. 200 19

Bryostatin 1 is a macrocyclic lactone which activates protein kinase C (PKC), and is able to induce maturation in cells from some cases of acute myelogenous leukemia. This paper reports that bryostatin inhibits the spontaneous in vitro proliferation of chronic myelomonocytic leukemia cells (CMMoL) in semi-solid medium at concentrations between 10(-8) and 10(-10) M. Growth inhibition was equivalent to or greater than that seen with phorbol-12-myristate-13-acetate. Bryostatin acted primarily as a cytotoxic agent, rather than as a cytostatic agent. The spontaneous in vitro proliferation of CMMoL cells is due to autocrine or paracrine secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). Bryostatin 1 actually increased GM-CSF secretion by CMMoL cells while inhibiting their proliferation. Bryostatin 1 also increased tumor necrosis factor alpha (TNF alpha) secretion by CMMoL cells, and in 2/5 cases the cytotoxic effect of bryostatin 1 on fresh CMMoL cells could be substantially reversed by the addition of antibody to TNF alpha to the culture medium. Bryostatin 1 may produce a cytotoxic effect on CMMoL cells in part by increasing the secretion of, or sensitivity to, TNF alpha, and may have therapeutic potential in CMMoL.
Leukemia 1991 Apr
PMID:Bryostatin 1: a potential anti-leukemic agent for chronic myelomonocytic leukemia. 202 97

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>