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

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the principal functions of erythropoietin (EPO) is to stimulate the maturation of erythroid precursors. Yet EPO has recently been shown to modulate a host of cellular signal transduction pathways in pluripotent stem cells to perform multiple functions other than erythropoiesis. The production of EPO is tightly modulated by the loss of oxygen and the hypoxia-inducible factor 1. Once generated, EPO becomes a robust stimulus which regulates endothelial cell proliferation and migration as well as erythropoiesis and vascular resistance. Further downstream in the signal transduction cascade, EPO engages diverse cellular pathways--such as those involving Janus kinase 2, signal transducers and activators of transcription (STATs), mitogen-activated protein kinases (MAPKs), Bcl-x(L), protein kinase B, protein kinase C, and cysteine proteases--to provide "plasticity" to vascular systems through highly conserved mechanisms. EPO also has recently been demonstrated to inhibit the induction of apoptosis through two distinct components that involve the maintenance of the integrity of genomic DNA and the preservation of cellular membrane asymmetry. Recognition of the multipotential attributes of EPO for vascular systems may further the progress of the development of therapeutic strategies to delay the onset of degenerative diseases.
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PMID:Angiogenesis and plasticity: role of erythropoietin in vascular systems. 1259 Jul 1

Telomerase is active in immature somatic cells, but not in differentiated cells. However, the mechanism by which telomerase is regulated in relation to cell differentiation is not well understood. In this study, the human erythroid leukemia cell line K562 was induced to differentiate into megakaryocytes by TPA and into erythroid by STI571. The human acute myeloblastic leukemia cell line HL60 was also induced to differentiate into monocytes by TPA. Telomerase activity, the expression of human telomerase reverse transcriptase, hTERT, and the cell cycle were examined. TPA induced a transient increase in telomerase activity during the megakaryocytic differentiation while the message of hTERT decreased gradually throughout the same period. This suggests the existence of a regulatory mechanism other than transcription of hTERT. Cell cycle analysis revealed that cells in G(2)/M phase increased in number in accordance with the changes in telomerase activity. Pretreatment with PKC inhibitors inhibited the megakaryocytic differentiation, transient increase in telomerase activity, and G(2)/M arrest. These results suggest that PKC acts as a transient post-translational activator of telomerase during megakaryocytic differentiation.
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PMID:Transient posttranslational up-regulation of telomerase activity during megakaryocytic differentiation of K562 cells. 1475 Dec 43

The G-protein-coupled receptor agonists CXCL12 (SDF-1, a chemokine) and thrombin showed opposite effects on growth and survival of multipotent and erythroid human hematopoietic progenitor cells. CXCL12 promoted growth in multipotent cells by activating the RhoA-Rho kinase pathway. Its effect was largely blocked by Y-27632, a specific inhibitor of Rho kinase, and by clostridial toxin B, a specific inhibitor of Rho family proteins. Rho activation required a G(i)-mediated stimulation of tyrosine kinases, which was blocked by PP2 and tyrphostin AG 490, inhibitors of Src and Jak type kinases, respectively. By contrast, in erythroid cells, inhibitors of Src family and c-Abl tyrosine kinases (tyrphostin AG 82, PP2, imatinib) enhanced protein kinase C (PKC)-dependent cell growth and antagonized thrombin-promoted apoptosis by specifically stimulating PKCbeta activity. The PKC activating phorbol ester PMA (a growth factor in erythroid cells) induced the activation of Lyn and c-Abl tyrosine kinases, thus establishing a feedback inhibition of PKCbeta. Hence, developmental stage-specific crosstalk between PKC subtypes and tyrosine kinases appear to determine whether growth and survival of hematopoietic cells are promoted or inhibited by G-protein-coupled receptor agonists.
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PMID:Two different pathways link G-protein-coupled receptors with tyrosine kinases for the modulation of growth and survival in human hematopoietic progenitor cells. 1560 23

One of the rational and effective strategies for chemoprevention is the blockade of DNA damage caused by carcinogenic insult. This can be achieved either by reducing the formation of reactive carcinogenic species or stimulating their detoxification. A wide spectrum of xenobiotic metabolizing enzymes catalyze both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions involved in carcinogen activation and/or deactivation. Several antioxidant-response element (ARE)-regulated gene products such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, UDP-glucuronosyltransferase, gamma-glutamate cysteine ligase, and hemeoxygenase-1 are known to mediate detoxification and/or to exert antioxidant functions thereby protecting cells from genotoxic damage. The transcription of ARE-driven genes is regulated, at least in part, by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2), which is sequestered in cytoplasm by Kelch-like ECH-associated protein 1 (Keap1). Exposure of cells to ARE inducers results in the dissociation of Nrf2 from Keap1 and facilitates translocation of Nrf2 to the nucleus, where it heterodimerizes with small Maf protein, and binds to ARE, eventually resulting in the transcriptional regulation of target genes. The Nrf2-Keap1-ARE signaling pathway can be modulated by several upstream kinases including phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases. Selected Nrf2-Keap1-ARE activators, such as oltipraz, anethole dithiolethione, sulforaphane, 6-methylsulphinylhexyl isothiocyanate, curcumin, caffeic acid phenethyl ester, 4'-bromoflavone, etc. are potential chemopreventive agents. This mini-review will focus on a chemopreventive strategy directed towards protection of DNA and other important cellular molecules by inducing de novo synthesis of phase II detoxifying or antioxidant genes via the Nrf2-ARE core signaling pathway.
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PMID:Nrf2 as a novel molecular target for chemoprevention. 1591 68

Apoptosis plays a central role in the regulation of the size of the hematopoietic stem cell pool as well as in the processes of cell differentiation along the various hematopoietic lineages. TRAIL is a member of the TNF family of cytokines with a known apoptogenic role against a variety of malignant cells and an emerging role in the modulation of normal hematopoiesis. Here we worked on the hypothesis that PKCepsilon could act as a switch of the cellular response to TRAIL during erythropoiesis. We demonstrate that EPO-induced erythroid CD34 cells are insensitive to the apoptogenic effect of TRAIL at day 0 due to the lack of specific receptor expression. From day 3 onward, erythroid cells express surface death receptors and become sensitive to TRAIL up to day 7/8 when, notwithstanding death-receptor expression, the EPO-driven up-regulation of PKCepsilon intracellular levels renders differentiating erythroid cells resistant to TRAIL likely via Bcl-2 up-regulation. Our conclusion is that in human CD34 cells, EPO promotes a series of events that, being finely regulated in their kinetics, restricts the sensitivity of these cells to TRAIL to a specific period of time, which therefore represents the "TRAIL window" for the negative regulation of erythroid-cell numbers.
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PMID:PKCepsilon controls protection against TRAIL in erythroid progenitors. 1616 86

The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.
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PMID:A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis. 1618 97

Gamma-glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5'-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epithelial cells, and that it could be induced by 4-hydroxynonenal (HNE) through the electrophile response element (EpRE) located in GGT promoter 5 (GP5). Here, we report transcription factors binding to GP5 EpRE and the involved signaling pathways. Immunodepletion gel shift assays demonstrated that GP5 EpRE bound JunB, c-Jun, FosB, and Fra2 from unstimulated cells, and that after exposure to HNE, EpRE binding complexes contained nuclear factor erythroid 2-related factor (Nrf) 1, Nrf2, JunB, c-Jun, FosB, c-Fos, Fra1, and Fra2. HNE-induced binding of Nrf2 and c-Jun in GP5 EpRE was confirmed by chromatin immunoprecipitation assays. Using reporter assays and specific inhibitors, we found that HNE induction of rat GGT mRNA V-2 was dependent on activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not protein kinase C or phosphatidylinositol 3-kinase. Pretreatment with ERK and p38MAPK inhibitors also blocked HNE-increased EpRE binding. HNE-increased nuclear content of Nrf1, Nrf2, and c-Jun in L2 cells was partially blocked by inhibition of either ERK1/2 or p38MAPK and completely blocked by simultaneous inhibition of both MAPKs. In conclusion, HNE induces GGT mRNA V-2 through altered EpRE transcription factor binding mediated by both ERK and p38MAPK.
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PMID:4-Hydroxynonenal induces rat gamma-glutamyl transpeptidase through mitogen-activated protein kinase-mediated electrophile response element/nuclear factor erythroid 2-related factor 2 signaling. 1619 35

One of the most prominent strategies of cancer chemoprevention might be protecting cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. This protection could be achieved through the induction of phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1, a process that is mediated mainly by the antioxidant response elements (ARE) within the promoter regions of these genes. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap 'n' collar (CNC) family of basic region-leucine zipper transcription factors, plays a key role in ARE-mediated gene expression. Under normal condition, Nrf2 is sequestered in the cytoplasm by an actin-binding protein, Kelch-like ECH associating protein 1 (Keap1), and upon exposure of cells to inducers such as oxidative stress and certain chemopreventive agents, Nrf2 dissociates from Keap1, translocates to the nucleus, binds to AREs, and transactivates phase 2 detoxifying and antioxidant genes. Several upstream signaling pathways including mitogen-activated protein kinases, protein kinase C, phosphatidylinositol 3-kinase, and transmembrane kinase are implicated in the regulation of Nrf2/ARE activity. Furthermore, many natural chemopreventive agents are known to induce Nrf2/ARE-dependent gene expression, also in part by regulating the turnover of the Nrf2 protein itself. This review discusses our current understanding of the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention, as well as the feasibility of screening natural compounds for activation of this pathway and as potential cancer preventive agents for human use.
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PMID:Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. 1648 42

CD163, the hemoglobin-haptoglobin receptor, has been reported to be expressed exclusively on monocyte/ macrophages. Here we demonstrate that CD163 is also expressed by a subpopulation of hematopoietic stem/progenitor cells. Flow cytometric analysis shows that 1.9 +/- 1.3% (+/-SD, n = 16) of adult bone marrow and 2.0 +/- 1.8% (n = 8) of umbilical cord blood CD34(+) cells express cell-surface CD163, and 69.1 +/- 16.9% (n = 9) and 79.7 +/- 22.4% (n = 8) of the respective cells contain the CD163 protein intracellularly. The expression of CD163 by CD34(+) cells was confirmed by western blot analysis of cell lysates. Transcripts corresponding to the known predominant and variant 1 forms of CD163 were amplified via RT-PCR from CD34(+) cell-derived mRNA. A new variant (K11) with a deletion at the start of exon 15 was also detected. The deleted region contains a PKCalpha phosphorylation site and an amino acid sequence (YREM) that may support efficient receptor endocytosis. The addition of activating anti-CD163 antibodies increased the growth and differentiation of erythroid progenitors in colony-forming assays. These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.
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PMID:Expression of the hemoglobin-haptoglobin receptor CD163 on hematopoietic progenitors. 1652 61

The regulation of the hematopoietic stem cell pool size and the processes of cell differentiation along the hematopoietic lineages involve apoptosis. Among the different factors with a recognized activity on blood progenitor cells, TRAIL - a member of the TNF family of cytokines - has an emerging role in the modulation of normal hematopoiesis.PKC(epsilon) levels are regulated by EPO in differentiating erythroid progenitors and control the protection against the apoptogenic effect of TRAIL. EPO-induced erythroid CD34 cells are insensitive to the apoptogenic effect of TRAIL between day 0 and day 3, due to the lack of specific surface receptors expression. Death receptors appear after day 3 of differentiation and consequently erythroid cells become sensitive to TRAIL up to day 9/10, when the EPO-driven up-regulation of PKC epsilon intracellular levels inhibits the TRAIL-mediated apoptosis, via Bcl-2. In the time interval between day 3 and 9, therefore, the number of erythroid progenitors can be limited by the presence of soluble or membrane-bound TRAIL present in the bone marrow microenvironment.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) and erythropoiesis: a role for PKC epsilon. 1658 80


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