Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal counterparts of the B cells found in hairy cell leukemia (HCL) are not known. We report here a detailed morphological, cytochemical, immunological and molecular analysis of a patient with B-cell chronic lymphocytic leukemia (B-CLL) who later in the course of his disease developed hairy cell leukemia. We speculate that hairy cell transformation of B-CLL might be related to an in vivo protein kinase C mediated cellular activation of B-CLL cells.
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PMID:Hairy cell transformation of a B-cell chronic lymphocytic leukemia: a morphological, cytochemical, phenotypic and molecular study. 167 87

The protooncogene product, Raf-1, is a serine/threonine kinase and has been implicated as an intermediate in signal transduction mechanisms. We examined neoplastic and normal B cells for phosphorylation and activation of Raf-1 protein in response to anti-immunoglobulin antibody (anti-Ig). Anti-Ig induced rapid phosphorylation of Raf-1 protein in both neoplastic B-cells of hairy cell leukemia and normal tonsillar B-cells which proliferated well in response to anti-Ig. The increase in phosphorylation was due primarily to an increase in phosphoserine. The immune complex kinase assay using Histone V-S as an exogenous substrate also showed an increase in Raf-1-associated kinase activity. An inhibitor of protein kinase C, H7, inhibited the proliferation as well as the Raf-1 phosphorylation in response to the proliferative signal of anti-Ig. Further, downregulation of protein kinase C by the treatment with 12-phorbol 13-myristic acid significantly abrogated the induction of Raf-1 phosphorylation. These results suggest that, in human B-cells, Raf-1 protein may be involved in the signal transduction pathway mediated by surface immunoglobulin, and that it may be, at least partially, phosphorylated by activated PKC.
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PMID:Surface immunoglobulin-mediated signal transduction involves rapid phosphorylation and activation of the protooncogene product Raf-1 in human B-cells. 173 44

We have investigated the motility, superoxide anion production and tumor cell lysis of neutrophils from five patients affected by hairy cell leukemia. Random locomotion and chemotaxis towards denaturated casein and activated serum was normal as well as the superoxide production by opsonized zymosan. In contrast, chemotaxis and superoxide generation induced by FMLP and TPA were markedly reduced. The low responsiveness of neutrophils to TPA was also observed by evaluating cell lysis, against either non-immunized K562 target cells or antibody-coated tumor targets. In hairy cell leukemia neutrophils showed a selective reduced response to TPA and FMLP that, directly or indirectly, activate PKC, suggesting an impairment in the system of signal transduction.
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PMID:Neutrophil defect associated with hairy cell leukemia. 196 34

Peripheral blood lymphocytes from patients with chronic lymphocytic leukemia (CLL) acquire after several days of exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) several morphological, immunological and histochemical features of hairy cell leukemia. We have investigated the short term effects of TPA treatment on protein kinase C and its subcellular distribution. Within minutes of addition of TPA to CLL cells 20% of the cytosolic protein kinase C had associated with the particulate fraction. The remaining 80% of protein kinase C activity was down-regulated. The association with the membrane dramatically increased the resistance of the enzyme to inhibition by the non-ionic detergent, Triton X-100. These results suggest that activation of protein kinase C causes multiple biological changes in CLL cells.
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PMID:Rapid down-regulation of protein kinase C and membrane association in phorbol ester-treated leukemia cells. 404 97

Malignant B lymphocytes from patients with B-chronic lymphocytic leukaemia (B-CLL) or hairy cell leukemia (HCL) are refractory in vitro to mitogenic stimulation by several agents which trigger proliferation of normal B cells. Tumour necrosis factor (TNF) is a growth factor for these malignant cells, although the proliferative response is usually small. TNF regulates some of its cellular responses via induction of the transcription factors NF kappa B and AP-1 (jun/fos). The induction of NF kappa B by TNF is mediated via a novel signalling pathway involving the generation of reactive oxidative intermediates. Induction of jun and fos proteins (polypeptide components of AP-1) are mediated via pathways involving protein kinase C and the protein kinase encoded by the raf proto-oncogene. Here we have used an electrophoretic mobility shift assay to show that TNF induced NF kappa B in malignant cells isolated from 3/3 HCL and 15/15 B-CLL patients. By contrast, phorbol myristate acetate (PMA), a direct activator of protein kinase C, failed to activate this transcription factor in 1/1 HCL and 5/5 B-CLL isolates. The induction of jun and fos proteins (as detected by Western blot analysis) showed greater heterogeneity. Nuclear jun was induced by TNF in 5/12 chronic B cell leukaemia isolates. PMA induced this protein in 4/5 samples. Nuclear fos was induced by TNF in only 2/12 isolates and by PMA in 2/5. The data suggest that the pathways for the activation of jun and fos by TNF are defective in some B-CLL and HCL cells and that these defects may be heterogeneous. The induction of AP-1 is crucial in securing the mitogenic response to TNF. It is therefore plausible that these lesions may contribute to the refractory nature of B-CLL and HCL cells to proliferative stimuli in vitro.
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PMID:Regulation of transcription factors NF kappa B and AP-1 following tumour necrosis factor-alpha treatment of cells from chronic B cell leukaemia patients. 804 32

Interferon-alpha (IFN-alpha) regulates the growth, differentiation, and recirculation of normal and malignant B lymphocytes. In this report we examine the effects of IFN-alpha on the distribution of the cytoskeletal protein spectrin in peripheral blood B lymphocytes from normal donors and patients diagnosed with chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). Exposure of normal and leukemic B cells to IFN-alpha in vitro was shown by immunofluorescence microscopy to cause a dose-dependent increase in the percentage of cells containing discrete focal accumulations of spectrin, ie, a single large aggregate or cap-like structure near the plasma membrane. Although the magnitude of this effect was variable among individual patient samples, in some experiments IFN-alpha induced a fourfold increase in the percentage of leukemic B cells exhibiting focal accumulations of spectrin. Spectrin reorganization induced by IFN-alpha was abrogated by the protein synthesis inhibitor cycloheximide. In addition, IFN-alpha increased the total cellular content of spectrin in B-CLL cells by approximately twofold to fourfold. Finally, a role for protein kinase C in mediating the effects of IFN-alpha on spectrin's organization is implicated by studies in which calphostin C inhibited the IFN-induced focal accumulation of spectrin. Taken together, these studies suggest that the immunomodulatory activities of IFN-alpha in normal and malignant B cells involve a change in the organization of the spectrin-based cytoskeleton.
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PMID:Interferon-alpha alters spectrin organization in normal and leukemic human B lymphocytes. 842 67

B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells are refractory to many of the signals which activate normal B cells but are stimulated to proliferate by tumor necrosis factor (TNF). Cell signalling by TNF is mediated in part by the induction of the transcription factor families AP-1 and NF-kappa B. In some cellular contexts, these factors play a role in regulating cell cycle transit. AP-1 binds DNA as dimers of jun and fos family proteins and is regulated by a cascade of protein kinases which eventually activate a mitogen-activated protein kinase (MAP kinase) and also by protein kinase C. Three pathways have been implicated in the activation of NF-kappa B by extracellular ligands. 1, the activation of protein kinase C by diacylglycerol generated by ligand-mediated activation of phosphatidylcholine hydrolysis, 2, stimulation of specific protein kinases by ceramide generated following activation of a sphingomyelinase by diacylglycerol and 3, a novel pathway involving ligand-induced generation of free radical species. In B-CLL and HCL cells, the generation of nuclear-localized c-jun and c-fos proteins (components of AP-1) in response to TNF or PMA appears to be blocked. Whereas PMA failed to induce NF-kappa B in these cells, this factor was readily induced by TNF. TNF induction of NF-kappa B was abolished by antioxidants, suggesting involvement of the free radical pathway. The data discussed here suggest defects in coupling of some protein kinase C-dependent pathways in B-CLL and HCL cells and that TNF is able to bypass these blocks by the activation of NF-kappa B via a free radical-dependent pathway which is independent of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Defects in signal transduction pathways in chronic B lymphocytic leukemia cells. 858 Aug 20

Infrared (IR) spectroscopy was used to compare the drug resistance mechanism of cells from chronic lymphocytic leukemia (CLL) patients with that of WSU-CLL cells. Bryostatin 1 (Bryo 1), a macrocyclic lactone and protein kinase C activator, was used to render WSU-CLL cells more susceptible to 2-chlorodeoxyadenosine (2-CdA). The IR spectroscopic analysis revealed some changes in protein and DNA content in Bryo 1-treated WSU-CLL cells, however, the most significant alterations were observed in the membrane lipids, which resemble those found between 2-CdA-sensitive and 2-CdA-resistant cells from CLL patients. In addition, Bryo 1 treatment induced WSU-CLL cells to become CD11c, CD25 and tartrate-resistant acid phosphatase-positive, specific markers for hairy cell leukemia, a disease exquisitely sensitive to 2-CdA. Our results suggest that 2-CdA-sensitive CLL cells have cellular characteristics resembling the hairy cell stage. The similarity between the membrane lipids in 2-CdA-sensitive CLL cells and the Bryo 1-treated WSU-CLL cell line supports the suggestion that membrane lipid alteration might be an important step in the drug resistance mechanism of CLL cells.
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PMID:Similarities between the sensitivity to 2-chlorodeoxyadenosine of lymphocytes from CLL patients and bryostatin 1-treated WSU-CLL cells: an infrared spectroscopic study. 961 76

We have previously identified the presence of Ras/Raf-independent constitutive activation of extracellular signal-regulated kinase (ERK) in the hairy cells (HCs) of hairy cell leukemia. The aim of the present study was to characterize the signaling components involved in this activation and their relationship to the reported activation of Rac1. We found that both Rac1 and ERK activation in HCs are downstream of active Src and protein kinase C (PKC). Inhibition with toxin B showed that Rac1 plays no role in ERK activation in HCs. However, toxin B inhibited p60src and the Rac1-GEF Vav, demonstrating a positive feedback/activation of p60src by Rac1. Treatment with specific small interfering RNA for various PKC isoforms, or with PKC isoform-specific inhibitors, demonstrated a central role for PKCepsilon in the constitutive activation of Rac1 and ERK in HCs. PKCepsilon and active ERK were mutually associated and co-localized with mitochondria in HCs. Furthermore, active PKCepsilon was nitrated on tyrosine, pointing to a reactive oxygen species-dependent mechanism of activation. By being involved in activation of ERK and Rac1, PKCepsilon plays roles in both the survival of HCs and in the cytoskeletal dynamics responsible for the distinctive morphology and tissue homing of these cells. Our study therefore describes novel aspects of signaling important for the pathogenesis of hairy cell leukemia.
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PMID:Central role of protein kinase Cepsilon in constitutive activation of ERK1/2 and Rac1 in the malignant cells of hairy cell leukemia. 1725 40

Chronic lymphoid leukemias include well defined mature B-cell and T-cell neoplasms with diverse natural history and specific morphological, immunophenotypic and molecular characteristics. The most common adult leukemia in the Western world is chronic lymphocytic leukemia (CLL). Rarer indolent lymphoid leukemias include prolymphocytic leukemia, hairy cell leukemia, large granular lymphocyte leukemia and T-cell leukemia/lymphoma. Recently, several new agents have been explored and have shown promise in CLL treatment. Novel therapies are being evaluated both in pre-clinical studies and in early clinical trials. These treatments include new purine nucleoside analogs, antisense oligonucleotides, agents targeting the antiapoptotic Bcl-2 family of proteins, receptors involved in mediation of survival signals from the microenvironment, cyclin-dependent kinase inhibitors, protein kinase C inhibitors, tyrosine kinase inhibitors, immunomodulating drugs, new monoclonal antibodies and other agents. At present, available therapies are only partially efficient and there is an obvious need to develop better strategies and new, more specific and active drugs. This review will focus on agents currently being explored in preclinical studies and in early clinical trials.
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PMID:Novel drugs for chronic lymphoid leukemias: mechanism of action and therapeutic activity. 1951 88


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