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)

Protein kinase C activators and microtubule-damaging drugs stimulate BCL2 phosphorylation, which has been associated with either enhancement or inhibition of cell viability. In a Burkitt lymphoma cell line, both types of agents likewise stimulated phosphorylation of myeloid cell leukemia 1 (MCL1), another viability-promoting BCL2 family member. However, while MCL1 phosphorylation induced by the protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), did not affect its electrophoretic mobility, microtubule-damaging agents, such as taxol, induced MCL1 phosphorylation associated with a band shift to decreased mobility. Inhibitors of extracellular signal-regulated kinase (ERK) activation blocked TPA-induced MCL1 phosphorylation but not the taxol-induced band shift. TPA-induced MCL1 phosphorylation occurred rapidly and was not associated with decreased viability, while the taxol-induced band shift occurred upon extended exposure as cells accumulated in G(2)/M followed by cell death. Protein phosphatase 1/2A inhibitors also induced the MCL1 band shift/phosphorylation. Thus, MCL1 undergoes two distinct types of phosphorylation: (i) TPA-induced, ERK-associated phosphorylation, which does not alter the electrophoretic mobility of MCL1, and (ii) ERK-independent phosphorylation, which results in an MCL1 band shift and is induced by events in G(2)/M or protein phosphatase 1/2A inhibitors.
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PMID:Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal-regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition. 1077 89

Mistletoe lectins (MLs) are increasingly used as an anticancer drug in the treatment of human tumors. The cytotoxic activity of MLs against tumor cells is due to programmed cell death (apoptosis). The up- or down-regulation of protein kinase A (PKA) or C (PKC) is known to be associated with the regulation of drug-induced apoptosis. Previously, we isolated cytotoxic MLII from the extract of Korean mistletoe (Viscum album var. Coloratum) and characterized its biochemical properties. The present study was designed to investigate the role of PKA and PKC in MLII-induced apoptosis. Exposure of human leukemia HL-60 cells to various doses of MLII resulted in apoptosis. However, the treatment of these cells with dibutyl-cyclic AMP (DB-cAMP), PKA activator, or 12-O-tertadecanoyl phorbol 13-acetate (TPA), PKC activator, suppressed MLII-induced apoptosis. Furthermore, KT5720 and staurospoline, PKA and PKC inhibitors, respectively, reversed the suppression by DB-cAMP and TPA in the MLII-induced apoptosis of HL-60 cells. These results suggest that the activation of PKA or PKC was involved in the suppression of MLII-induced apoptosis in HL-60 cells. Collectively, these results indicate that activation of PKA or PKC in HL-60 cells may confer protection against MLII-induced apoptosis.
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PMID:Protein kinase A or C modulates the apoptosis induced by lectin II isolated from Korean mistletoe, Viscum album var. Coloratum, in the human leukemic HL-60 cells. 1095 32

The Notch genes of C. elegans, Drosophila melanogaster and vertebrates encode receptors responsible for cell fate decisions during development. These Notch receptors and their ligands, Delta and Jagged, have been implicated in several human diseases. Truncated, constitutively active mutant forms of the Notch receptor appear to be involved in human T-cell leukemia, mammary carcinomas in mice, and a tumorous germline phenotype in C. elegans. Since activated Notch induces solitary tumors in transgenic mice, it is highly likely that collaborating genetic events are required for tumor formation. We have assessed four signal transduction pathways to determine which might play additional roles in malignant transformation in concert with activated Notch4. Our results suggest that transformation by Notch does not, as might have been expected, depend on the Src-like kinases Lck and Fyn, nor upon signals from protein kinase A and C (PKA, PKC). Rather, transformation by Notch requires active signals from the Erk/MAP kinase and PI-3 kinase pathways downstream of Ras. Oncogene (2000) 19, 4191 - 4198
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PMID:Ras pathway signals are required for notch-mediated oncogenesis. 1098 May 92

Cells sense and respond to extracellular factors via receptors on the cell surface that trigger intracellular signaling pathways. The signals received by the receptors on hematopoietic cells often determine if the cell proliferates, survives or undergoes apoptosis. Apoptosis can be induced by almost any cytotoxic stimuli. These stimuli may be an absence of signals arising from cellular receptors, stimulation of specific ligand receptors on the cell surface, chemotherapeutic agents, and ionizing radiation or oxygen radicals, as well as a number of other factors. Cellular kinases and phosphatases participate in signaling cascades that influence this process. We review the ability of the calmodulin-dependent-kinases, I-kappaB kinases, PI3-kinases, Jakkinases, PKC, PKA, and MAP kinase signaling pathways (Erk, Jnk, and p38), to influence the apoptotic process. In addition, we discuss the cross-talk that exists between signaling cascades that are pro-apoptotic and anti-apoptotic.
Leukemia 2000 Dec
PMID:Kinases: positive and negative regulators of apoptosis. 1118 89

Interactions between the purine analogue 2-fluoroadenine 9-beta-D-arabinofuranoside (F-ara-A) and the kinase inhibitor UCN-01 have been examined in human leukemia cells (U937 and HL-60) with respect to induction of mitochondrial damage, caspase activation, apoptosis, and loss of clonogenic survival. Simultaneous or subsequent exposure of F-ara-A-treated cells (2 microM) to UCN-01 (100 nM) resulted in a marked potentiation of apoptosis, manifested by loss of mitochondrial membrane potential (delta psi(m)), cleavage/activation of procaspase-9 and procaspase-3, DNA fragmentation, and degradation of poly-ADP(ribosyl) polymerase. Coadministration of UCN-01 with F-ara-A was also associated with diminished phosphorylation of the cdc25 phosphatase. In contrast, exposure of cells to the sequence UCN-01, followed by F-ara-A, resulted in only a modest increase in apoptotic cells. The ability of UCN-01 to potentiate F-ara-A-mediated lethality was not mimicked by the selective PKC inhibitor bisindolylmaleimide, nor did treatment of cells with UCN-01 enhance formation of F-ara-ATP or increase incorporation of [3H]F-ara-A into DNA. Enhanced apoptosis in cells exposed sequentially or simultaneously to F-ara-A and UCN-01 was accompanied by a substantial reduction in colony formation (e.g., to 0.01% of control values). Cotreatment with UCN-01 also increased F-ara-A-mediated apoptosis and loss of delta psi(m) in U937 cells ectopically expressing Bcl-2, although not to the same extent as that observed in empty-vector controls. Finally, simultaneous exposure (24 h) of malignant B lymphocytes from the pleural effusion of a patient with indolent non-Hodgkin's lymphoma to F-ara-A and UCN-01 ex vivo resulted in a striking increase in apoptosis, as determined by terminal deoxynucleotidyltransferase-mediated nick end labeling assay. These findings indicate that UCN-01 increases F-ara-A-induced mitochondrial damage and apoptosis in human leukemia cells in a sequence-dependent manner, and that these events occur in at least some primary human lymphoma cells.
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PMID:Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells. 1123 87

The role of protein kinases on store-operated Ca2+ entry in rat basophilic leukaemia cells (RBL) has been studied using the whole-cell configuration of the patch-clamp technique and Ca2+ imaging with fura-2. Specific inhibitors of tyrosine kinase (lavendustin A), mitogen-activated protein (MAP) kinase (SB 203580, PD 98059), Ca2+/calmodulin-dependent kinase (CaMK, KN-62, KN-93) and protein kinase C (PKC, bisindolylmaleimide I) had no significant effect on peak current amplitude and time constant of activation. Likewise, the broad spectrum kinase blockers H-7 and staurosporine did not alter Ca2+ entry compared to control recordings. Store-mediated Ca2+ entry was unaffected if intracellular ATP was substituted by either adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS) or adenylyl-imidodiphosphate (AMP-PNP). Similarly, buffering intracellular Mg2+, an essential cofactor for protein kinases, had no effect on Ca2+ influx. These results indicate that protein phosphorylation by various kinases is not required for the activation of the store-operated Ca2+ current in RBL cells.
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PMID:Activation of store-operated Ca2+ entry in RBL cells without the contribution of protein kinases. 1141 58

Vitamin E-succinate (VES) induced HL-60 human leukemia cells to undergo apoptosis. Treatment with VES induced membrane translocation of Fas; cleavages of caspase-3, PARP, and lamin B; hypophosphorylation of retinoblastoma protein; and increase of p21(WAF1) protein level. During the induction of apoptosis, activity of PKC was gradually increased with downregulation of VES-induced ERK activity and accompanied by activation of caspase-3. Inhibition of PKC by GF109203X blocked VES-mediated membrane translocation of PKC-alpha and cleavage of caspase-3 cascade, resulting in prevention of VES-induced apoptosis. On the contrary, PKC activation by cotreatment with LPC or thapsigargin and VES synergistically increased VES-mediated apoptosis. However, inhibition of ERK activity by PD98059 showed no significant effect on VES-induced PKC activity and apoptosis. Taken together, our data suggest that VES induces activation of PKC and PKC-dependent hypophosphorylation of retinoblastoma protein, which results in induction of apoptosis, and that VES-induced early activation of ERK and ERK-dependent induction of p21(WAF1) are not required for apoptosis.
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PMID:Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells. 1168 77

Protein kinase C (PKC) is known to activate NF-kappaB whereas the lipid mediator ceramide was recently shown to inhibit activation of this transcription factor (1, 2). In this study, the mechanisms by which ceramide interferes with this pathway were examined in Jurkat leukemia and MCF-7 breast cancer cells. Both exogenous and endogenous ceramide inhibited selectively PKC-mediated activation of NF-kappaB by reverting PKC translocation to the membrane. Next, confocal and immunofluorescence studies were performed to evaluate the direct effects of ceramide on PKC. These studies showed that ceramide inhibited translocation of a green fluorescent protein (GFP)-PKCbeta2 fusion protein in response to PMA. A mutant PKC in which autophosphorylation sites were mutated to alanine (PKC-DA) was resistant to ceramide. A kinase-inactive mutant (PKC-KR) was also resistant to ceramide action, and the results were supported using kinase inhibitors of the enzyme. Finally, overexpression of PKC-DA prevented, at least partly, the ability of ceramide to inhibit activation of NF-kappaB. Taken together, these studies show that ceramide has acute effects on translocation of PKC by inducing reverse translocation, and this reversal requires both the kinase activity of PKC and phosphorylation of the autophosphorylation sites.
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PMID:Ceramide inhibition of NF-kappaB activation involves reverse translocation of classical protein kinase C (PKC) isoenzymes: requirement for kinase activity and carboxyl-terminal phosphorylation of PKC for the ceramide response. 1168 65

HTLV-I is etiologically implicated with tropical spastic paraparesis/HTLV-I associated myelopathy, adult T-cell leukemia and certain other diseases. However, after infection the virus enters into a dormant state, whereas the characteristics of the HTLV-I related diseases indicate that their genesis requires activation of the dormant virus by a Tax-independent mechanism. In the present study we demonstrate that a variety of stress-inducing agents (TPA, cisplatin, etoposide, taxol, and 3-methylcholanthrene) are capable of Tax-independent activation of HTLV-I LTR and that this activation is detected mainly in cells that are undergoing through the apoptotic process. Furthermore, it is demonstrated that both apoptosis induction and HTLV-I LTR activation are inhibited by Bcl-2 and by PKC, indicating that these two processes are mechanistically cross-linked. In addition, using an HTLV-I producing human T-cell line which permanently express the negatively transdominant tax mutant, Delta58tax, under the Tet-Off control system, we prove that the virally encoded Tax protein protects the host cells from apoptosis. Together, these data suggest that activation of the dormant virus in the carriers' infected T-cells by certain stress-inducing conditions and protecting these cells from the consequent apoptotic death by the viral Tax protein emerging after this activation, might be the basis for switching the virus from latency to a pathogenic phase.
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PMID:Activation of HTLV-I long terminal repeat by stress-inducing agents and protection of HTLV-I-infected T-cells from apoptosis by the viral tax protein. 1169 93

Daphnane-type diterpene gnidimacrin (NSC252940), isolated from a Chinese plant, exhibited antitumor activity against murine leukemias and solid tumors. At concentrations of 10(-9) to 10(-10) M, this agent strongly inhibited the growth of human tumor cell lines. In sensitive human leukemia K562 cells, gnidimacrin is a PKC activator that arrests the cell cycle in the G(1) phase by inhibiting cdk2 activity. A 4 hr exposure of K562 cells to gnidimacrin induced the CDK inhibitor p21(WAF1/Cip1), but this effect was transient and did not correlate temporally with the onset of G(1) arrest. Expression of cdc25A, a phosphatase that activates cdk2, was reduced during 24-hr exposure to gnidimacrin. Moreover, the suppression corresponded in a concentration- and time-dependent manner to both the inhibition of cdk2 activity and the mobility shift observed when cdk2 was electrophoresed on SDS-PAGE, indicating that the phosphorylation state of cdk2 must change. Cyclin E, the other regulator of cdk2 activity, was not influenced by gnidimacrin. These results suggest that gnidimacrin exerts antitumor activity through suppression of cdc25A and inhibition of cdk2 activity.
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PMID:Antitumor action of the PKC activator gnidimacrin through cdk2 inhibition. 1174 13


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