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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human promyelocytic leukemia cell line HL-60 was induced to differentiate to mature granulocytic cells by dbcAMP or RA. The influence of distinct protein kinases during different stages of this differentiation was studied by the use of H8, staurosporine and genistein as inhibitors of PKA, PKC and PTK respectively. In dbcAMP-mediated differentiation, the PKA activity of uninduced cells is crucial for the induction of differentiation, but therefore its significance drastically declines and a more important role is played by PKC and PTK. In RA-mediated differentiation, the native state of PKA and PKC activities are necessary and of similar importance for induction. However, the differentiation is enhanced when, following induction, the activities of PKA and PTK are normal and the activity of PKC, in contrast, is temporary suppressed. At the phenotypic stage the effect of inhibition of protein kinases on maturation is in the order PTK > PKC > PKA for the dbcAMP-mediated differentiation and PKC > PKA > PTK for the RA-mediated differentiation. The results indicate that protein kinase activities during differentiation are stage specific and this specificity depends on the inducer used.
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PMID:Protein kinase inhibitors exert stage specific and inducer dependent effects on HL-60 cell differentiation. 764 44

The effect of the CSF-1 receptor, cFMS, on the phosphorylation of the retinoblastoma (RB) tumor suppressor protein and on the cell cycle and cell differentiation was analyzed in a cultured promyelocytic leukemia cell capable of induced myelomonocytic differentiation. A series of cFMS-transfected HL-60 sublines with progressively higher cell surface FMS expression was derived by flow cytometric cell sorting. Overexpression of FMS increased the duration of the cell cycle, prolonging all cell cycle phases especially S phase, which doubled. The increased cell cycle generation times occurred without any detectable changes in RB expression level or phosphorylation. For retinoic acid (RA)-induced myeloid differentiation, progressive overexpression of FMS caused a greater fraction of cells to differentiate and G1/0 arrest compared to wild-type cells after the same number of cell cycle generation times. FMS overexpression also progressively increased the relative amount of dephosphorylated RB protein induced, while reducing the total amount of RB protein. The inducer-originated and FMS-driven changes in RB hypophosphorylation were not effected through changes in p21/WAF1/CIP1 in this p53-negative cell. Similar effects on differentiation and G0 arrest occurred with 1,25-dihydroxy vitamin D3 (D3)-induced monocytic differentiation. FMS did not significantly affect myeloid differentiation induced by DMSO, which does not target steroid-thyroid hormone receptors like RA and D3. While differentiation is typically associated with hypophosphorylated RB in all these cases, the kinetics indicate that the FMS-induced changes in cell cycle and cell differentiation do not depend in a direct causal fashion on the interconversion between hyperphosphorylated and hypophosphorylated RB.
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PMID:FMS (CSF-1 receptor) prolongs cell cycle and promotes retinoic acid-induced hypophosphorylation of retinoblastoma protein, G1 arrest, and cell differentiation. 894 Feb 55

Stimulation of apoptosis induced by 1-(beta-D-arabinofuranosyl)cytosine (AraC) with protein kinase inhibitors (i.e. staurosporine, CGP 41251-a protein kinase C (PKC)-selective staurosporine derivative and protein tyrosine kinase (PKT) inhibitor genistein) was examined in two human multidrug-resistant promyelocytic leukemia (HL-60) cell lines with different cell membrane drug resistance-associated glycoproteins (i.e. HL-60/VCR:MDR1 gene coded Pgp/p170 and HL-60/ADR: MRP gene coded non-Pgp/p190). Staurosporine stimulated AraC-induced apoptosis in the parental drug-sensitive HL-60 cells and both examined multidrug resistant HL-60 sublines. The stimulation of AraC-induced apoptosis by PKC selective inhibitor CGP 412251 and PTK-inhibitor genistein was approximately equal to that of staurosporine in HL-60/ADR cell line. In both parental drug sensitive HL-60 cells and Pgp/p170 positive (MDR1) HL-60/VCR, staurosporine-stimulated AraC-induced apoptosis was higher than that stimulated by the PKC selective CGP 41251 inhibitor, or PTK-inhibitor genistein. These data suggest that the molecular pathway(s) for AraC-induced apoptosis can be activated and stimulated by PKC- and PTK-inhibitors in both examined drug-resistant HL-60 cell lines. Furthermore, these data suggest that although both PKC- and PTK-dependent mechanisms are involved in AraC-induced apoptosis, in the drug-sensitive HL-60 cells and multidrug-resistant HL-60/VCR (Pgp/p170) cells this process is mediated at least partially, also by PKC- and PTK-independent mechanisms, activated by staurosporine.
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PMID:Stimulation of 1-(beta-D-arabinofuranosyl)cytosine (AraC)-induced apoptosis in the multidrug resistant human promyelocytic leukemia cell lines with protein kinase inhibitors. 899 46

In the mouse, mutations at the natural resistance-associated macrophage protein 1 (Nramp1) gene abrogate resistance to infection with antigenically unrelated intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Nramp1 expression is restricted to reticuloendothelial organs and peripheral blood leukocytes, where the protein may function as a membrane transporter of an as yet to be identified substrate. To identify the human blood cell type(s) expressing NRAMP1 mRNA and determine how Nramp1 expression is regulated in these cells, we have examined separated populations of peripheral blood leukocytes and in vitro cell lines. We observed that polymorphonuclear leukocytes (PMN) are the major site of NRAMP1 expression, followed to a lesser degree by monocytes (MN). Migration of MN to tissues (alveolar macrophages) or maturation in vitro (long-term culture) was associated with a higher level of NRAMP1 expression compared with blood MN. Northern analyses of RNA from model cultured cells showed absence of NRAMP1 expression in transformed cell lines from either erythroid or lymphoid T or B lineages as well as progenitors of the monocyte/macrophage pathway (KG1, U937, THP1), and the HL-60 promyelocytic leukemia. Induction of differentiation of HL-60 cells toward either the monocyte/macrophage (vitamin D3, phorbol ester) or the granulocyte pathways (DMF, DMSO), as measured by induction of IL8-Rb, c-FMS, and CD14 marker gene expression, was concomitant with a strong induction of NRAMP1 expression. These results suggest that NRAMP1 expression is specific to the myeloid lineage and is acquired during the maturation of PMN and MN. The possibility that NRAMP1 may be a component of the phagosomal/endosomal apparatus common to PMN and MN is discussed.
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PMID:Expression of the human NRAMP1 gene in professional primary phagocytes: studies in blood cells and in HL-60 promyelocytic leukemia. 900 May 42

Eugenia jambos L. (Myrtaceae) is an antipyretic and anti-inflammatory herb of Asian folk medicine. A 70% acetone extract exerted the strongest cytotoxic effects on human leukemia cells (HL-60) from a preliminary screening of 15 plants. The cytotoxic principles were separated by bio-assay-guided fractionation to HL-60 cells; two hydrolyzable tannins (1-O-galloyl castalagin and casuarinin) were isolated from the 70% acetone extract. All significantly inhibited human promyelocytic leukemia cell line HL-60 and showed less cytotoxicity to human adenocarcinoma cell line SK-HEP-1 and normal cell lines of human lymphocytes and Chang liver cells. Thus, these compounds were exhibited the dose-dependent manner in HL-60 cells and the IC(50) were 10.8 and 12.5 microM, respectively. Flow cytometric analysis demonstrated the presence of apoptotic cells with low DNA content, a decrease of cell population at G(2)/M phase, and a concomitant increase of cell population at G(1) phase. The apoptosis induced by these two compounds was also demonstrated by DNA fragmentation assay and microscopic observation. These results suggest that the cytotoxic mechanism of both antitumor principle constituents might be the induction of apoptosis in HL-60 cells.
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PMID:Induction of apoptosis by hydrolyzable tannins from Eugenia jambos L. on human leukemia cells. 1089 44

Acquired chromosomal anomalies (most commonly translocations) in lymphoma and leukemia usually result in either activation of a quiescent gene (by means of immunoglobulin or T-cell-receptor promotors) and expression of an intact protein product, or creation of a fusion gene encoding a chimeric protein. This review summarizes current immunocytochemical studies of these 2 categories of oncogenic protein, with emphasis on the clinical relevance of their detection in diagnostic samples. Among the quiescent genes activated by rearrangement, expression of cyclin D1 (due to rearrangement of the CCND1 [BCL-1] gene) is a near-specific marker of t(11;14) in mantle cell lymphoma; BCL-2 expression distinguishes follicular lymphoma cells from their nonneoplastic counterparts in reactive germinal centers and appears to be an independent prognostic marker in diffuse large cell lymphoma; and TAL-1 (SCL) expression identifies T-cell acute lymphoblastic neoplasms in which this gene is activated. The protein products of other genes activated by chromosomal rearrangement have a role as markers of either lineage (eg, PAX-5 [B-cell-specific activator protein] for B cells, including B-lymphoblastic neoplasms), or maturation stage (eg, BCL-6 for germinal-center and activated B cells and MUM-1/IRF4 for plasma cells). Currently, no hybrid protein encoded by fusion genes is reliably detectable by antibodies recognizing unique junctional epitopes (ie, epitopes absent from the wild-type constituent proteins). Nevertheless, staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RARalpha is highly distinctive. Similarly, antibodies to the anaplastic lymphoma kinase (ALK) tyrosine kinase are valuable (because wild-type ALK is not found in normal lymphoid tissue) in detecting neoplasms (CD30-positive large T-cell lymphomas) with t(2;5) or its variants. Thus, immunocytochemical detection of the products of many rearranged genes in lymphoma and leukemia can be clinically informative and provide information on cellular and subcellular protein expression that cannot be inferred from studies based on messenger RNA.
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PMID:Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. 1178 Dec 20

Costunolide, a germacranolide sesquiterpene lactone that exists in several medicinal plants, is known to be a possible anti-cancer and chemopreventive agent for tumorigenesis. In this report, we investigated the effect of costunolide on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Costunolide markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with 5nM 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)). Costunolide by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that costunolide potentiated 1,25-(OH)(2)D(3)-induced cell differentiation predominantly into monocytes. Inhibitors for PKC, PI3-K, and ERK markedly inhibited HL-60 cell differentiation induced by costunolide in combination with 1,25-(OH)(2)D(3). In addition, pretreatment of HL-60 cells with costunolide before the 1,25-(OH)(2)D(3) addition also potentiated cell differentiation in a concentration- and time-dependent manner, and the enhanced levels of cell differentiation closely correlated with the inhibitory levels of NF-kappaB-binding activity by costunolide. These results indicate that PKC, PI3-K, ERK and NF-kappaB may be involved in 1,25-(OH)(2)D(3)-mediated cell differentiation enhanced by costunolide.
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PMID:Potentiation of 1,25-dihydroxyvitamin D(3)-induced differentiation of human promyelocytic leukemia cells into monocytes by costunolide, a germacranolide sesquiterpene lactone. 1223 4

Tissue engineering may offer patients new options when replacement or repair of an organ is needed. However, most tissues will require a microvascular network to supply oxygen and nutrients. One strategy for creating a microvascular network would be promotion of vasculogenesis in situ by seeding vascular progenitor cells within the biopolymeric construct. To pursue this strategy, we isolated CD34(+)/CD133(+) endothelial progenitor cells (EPC) from human umbilical cord blood and expanded the cells ex vivo as EPC-derived endothelial cells (EC). The EPC lost expression of the stem cell marker CD133 but continued to express the endothelial markers KDR/VEGF-R2, VE-cadherin, CD31, von Willebrand factor, and E-selectin. The cells were also shown to mediate calcium-dependent adhesion of HL-60 cells, a human promyelocytic leukemia cell line, providing evidence for a proinflammatory endothelial phenotype. The EPC-derived EC maintained this endothelial phenotype when expanded in roller bottles and subsequently seeded on polyglycolic acid-poly-l-lactic acid (PGA-PLLA) scaffolds, but microvessel formation was not observed. In contrast, EPC-derived EC seeded with human smooth muscle cells formed capillary-like structures throughout the scaffold (76.5 +/- 35 microvessels/mm(2)). These results indicate that 1) EPC-derived EC can be expanded in vitro and seeded on biodegradable scaffolds with preservation of endothelial phenotype and 2) EPC-derived EC seeded with human smooth muscle cells form microvessels on porous PGA-PLLA scaffolds. These properties indicate that EPC may be well suited for creating microvascular networks within tissue-engineered constructs.
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PMID:Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells. 1527 91

Extracts of Artemisia asiatica Nakai (Asteraceae) possess anti-inflammatory and anti-oxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone), one of the pharmacologically active ingredients derived from A. asiatica, was shown to induce apoptosis in human promyelocytic leukemia (HL-60) cells [Mutat Res 496 (2001) 191]. In the present study, we examined the cytostatic effects of eupatilin in H-ras-transformed human breast epithelial (MCF10A-ras) cells. Eupatilin inhibited the growth of MCF10A-ras cells in a concentration-dependent and time-related manner. To explore whether the anti-proliferative effects of eupatilin could be mediated through modulation of the cell cycle in MCF10A-ras, DNA contents were analyzed by the flow cytometry. Eupatilin inhibited the expression of cyclin D1, cyclin B1, Cdk2 and Cdc2 that are key regulators of the cell cycle. In addition, eupatilin treatment led to elevated expression of p53 and p27Kip1 that act as Cdk inhibitors. It has been known that the Ras-signaling pathway plays integral roles in the induction of cyclin D1. Eupatilin inhibited the activation of ERK1/2 as well as expression of Raf-1 and Ras in MCF10A-ras cells. Thus, the inhibitory effect of eupatilin on cyclin D1 expression appears to be mediated by targeting the Raf/MEK/ERK signaling cascades. Eupatilin did not change activation of Akt, an important component of cell-survival pathways. In conclusion, the anti-proliferative effect of eupatilin in MCF10A-ras cells is associated with its blockade of cell cycle progression which appears to be attributable in part to inhibition of ERK1/2 activation.
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PMID:Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces cell cycle arrest in ras-transformed human mammary epithelial cells. 1531 4

Human neutrophils exhibit a regulated phospholipase D (PLD) activity that can be measured biochemically in vitro. However, the precise expression pattern of PLD isoforms and their specific biological role(s) are not well understood. Neutrophil mRNA is intrinsically difficult to isolate as a result of the extremely high content of lytic enzymes in the cell's lysosomal granules. Reverse transcription coupled to polymerase chain reaction indicated that pure populations of human neutrophils had the CD16b(+)/CD115(-)/CD20(-)/CD3zeta(-)/interleukin-5 receptor alpha(-) phenotype. These cells expressed the following splice variants of the PLD1 isoform: PLD1a, PLD1b, PLD1a2, and PLD1b2. As for the PLD2 isoform, neutrophils expressed the PLD2a but not the PLD2b mRNA variant. The relative amount of PLD1/PLD2 transcripts exists in an approximate 4:1 ratio. The expression of PLD isoforms varies during granulocytic differentiation, as demonstrated in the promyelocytic leukemia HL-60 cell line. Further, the pattern of mRNA expression is dependent on the differentiation-inducing agent, 1.25% dimethyl sulfoxide causes a dramatic increase in PLD2a and PLD1b transcripts, and 300 nM all-trans-retinoic acid induced PLD1a expression. These results demonstrate for the first time that human neutrophils express five PLD transcripts and that the PLD genes undergo qualitative changes in transcription regulation during granulocytic differentiation.
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PMID:Phospholipase D (PLD) gene expression in human neutrophils and HL-60 differentiation. 1577 48


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