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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (HGF) secreted from human promyelocytic leukemia cell line, HL-60, is indistinguishable from HGF in human plasma and its release is significantly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a differentiation-inducer of HL-60 cells into monocytes/macrophages (Nishino T et al: Biochem Biophys Res Commun 181:323, 1991). TPA stimulated HGF release from the cells through an activation of C-kinase, but not through a formation of reactive oxygen species. Furthermore, dibutyryl cAMP (dbcAMP), an activator of A-kinase and granulocyte-inducer, also stimulated HGF release. 1,25-Dihydroxyvitamin D3, another monocyte/macrophage-inducer, abated either TPA- or dbcAMP-stimulated synthesis and release of HGF in a dose-dependent manner probably via its nuclear receptor as reflected by vitamin D analog study. The effects of these three reagents on the steady-state levels of HGF mRNA of 6.0 kb corresponded with their effects on its protein levels. Furthermore, a close correlation between intracellular and extracellular HGF levels strongly suggested that these reagents affected HGF release mainly on its synthesis step. Recombinant human HGF significantly stimulated the proliferation and alkaline phosphatase activity of mouse osteoblastic cell line, MC3T3-E1. In summary, HL-60 cells secrete HGF, whose synthesis is specifically regulated by various reagents independent of their differentiation-inducing effects. Because HGF shows a direct effect on osteoblast-like cells, it might be involved in the interaction of bone marrow cells with bone cells.
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PMID:Regulation of release of hepatocyte growth factor from human promyelocytic leukemia cells, HL-60, by 1,25-dihydroxyvitamin D3, 12-O-tetradecanoylphorbol 13-acetate, and dibutyryl cyclic adenosine monophosphate. 839 78

8-Cl-cAMP, a site-selective cAMP analog, induces growth inhibition in a variety of cell types of human cancer cell lines. This inhibitory effect of 8-Cl-cAMP was related to its ability to differentially regulate type I versus type II cAMP-dependent protein kinase. In the present study we demonstrated a unique mechanism of action of 8-Cl-cAMP in the regulation of these kinase isozymes in HL-60 human promyelocytic leukemia cells. High-performance liquid chromatography (HPLC) resolved various isoforms of protein kinase present in HL-60 cells. In control cells, type I protein kinase (PKI) comprised more than 90% and type II protein kinase (PKII) less than 10% of the total cAMP-stimulated kinase activity. Treatment with 8-Cl-cAMP (5 microM, 72 h) decreased PKI to a level below 30% of that in untreated control cells and markedly increased PKII composed of three peaks. Photoaffinity labeling/SDS-polyacrylamide gel electrophoresis of column fractions identified the molecular species of regulatory (R) subunits present in protein kinases. Control cells contained high levels of the 48-kDa protein (RI) that composed PKI and low levels of the 50-kDa RII associated with PKII. 8-Cl-cAMP treatment brought about a decrease in the 48-kDa RI along with an increased formation of the truncated 34-kDa RI associated with PKI and an increase in the 50-54-kDa species of RII associated with PKII. A similar protein kinase profile as that shown by 8-Cl-cAMP treatment was observed in cells infected with the human RII beta retroviral vector: the 48-kDa RI of PKI decreased and the 52- and 54-kDa RII associated with PKII increased as compared with uninfected control cells. However, unlike 8-Cl-cAMP treatment, RII beta retroviral vector infection brought about no increase in the 34-kDa-truncated RI but exhibited an increase in the free 48-kDa RI subunit. As the 48-kDa RI and the 50-kDa RII were present in control cells, the enhanced expression of the 52- and 54-kDa RII proteins was due to overexpression of the RII beta gene. We identified the 48-kDa RI as RI alpha, the 50-kDa RII as RII alpha, the 52-kDa RII as RII beta, and the 54-kDa RII as the phosphorylated form of either the RII alpha or RII beta subunit. In vivo labeling experiments using [3H]8-Cl-cAMP demonstrated that 8-Cl-cAMP enters cells and binds to both PKI and PKII.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:8-Cl-cAMP induces truncation and down-regulation of the RI alpha subunit and up-regulation of the RII beta subunit of cAMP-dependent protein kinase leading to type II holoenzyme-dependent growth inhibition and differentiation of HL-60 leukemia cells. 844 43

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

The influence of protein kinases on the differentiation of a human promyelocytic leukemia-cell line HL-60 to granulocytes was studied by using H8 and staurosporine as inhibitors of PKA and PKC respectively. In order to determine the significance of these protein kinases of uninduced and differentiating cells for the final differentiation, the cells were treated with the inhibitors before (-24 hours-0 hours) and after induction (0 hour-96 hours) of differentiation. To elucidate potential "cross-talking" between PKA and PKC of uninduced and differentiating HL-60 cells, the effects of H8 and staurosporine on differentiation were further examined by exposing the cells, pretreated with inhibitors for approximately one cell cycle time before induction, to the same or a different inhibitor. The results demonstrated that the effects of the inhibition of protein kinases of these cells on differentiation are protein kinase and inducer dependent. There is also inducer-dependent "cross-talk" between the differentiation mechanisms involving PKA and PKC activities in uninduced HL-60 cells and in cells induced to differentiate by dbcAMP or RA. However, the data also demonstrate that the PKC activity of uninduced cells involved in the differentiating mechanisms is not related to the PKC activity of dbcAMP-mediated differentiation and PKA is not related to PKC, respectively, in RA-mediated differentiation. The effects of the pretreatment of HL-60 cells with dbcAMP or RA for 24 hours on their subsequent differentiation induced by dbcAMP or RA are different. The pretreatment of cells with dbcAMP strongly potentiates RA-mediated differentiation, while the pretreatment with RA suppresses twofold dbcAMP-mediated differentiation.
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PMID:Relationship between differentiation mechanisms involving cAMP-dependent protein kinase and protein kinase C in uninduced and differentiating HL-60 cells. 906 66

Microbial extracellular glycolipids, succinoyl trehalose lipid (STL), and mannosylerythritol lipid (MEL) inhibited the growth of a human promyelocytic leukemia cell line, HL60, and induced their morphological changes. The results of specific and nonspecific leukocyte esterase activities showed that STL induced monocytotic differentiation while MEL induced granulocytic differentiation. STL and MEL markedly increased common differentiation-associated characteristics in monocytes and granulocytes, such as nitroblue tetrazolium (NBT) reducing ability, expression of Fc receptors, and phagocytic activities in HL60 cells, respectively. Neither sugar moieties nor fatty acids in the free form, the individual components of STL and MEL, were effective at inducing the differentiation of HL60 cells. The induction of differentiation was not due to surface activities of STL and MEL on the basis of the complete ineffectiveness of the analogues tested. The composition of cell surface glycosphingolipids (GSL) changed such that the GM3/LacCer ratio increased in STL-treated cells, whereas it decreased in MEL-treated cells. HL60 cells treated with STL and MEL exhibited a significant decrease in the activity of the intracellular phospholipid- and Ca(2+)-dependent protein kinase (protein kinase C). Furthermore, the serine/threonine phosphorylations in intact HL60 cells were clearly inhibited by the presence of GM3 and MEL, but not by LacCer and STL. These results suggest that the differentiation-inducing activity of STL and MEL is not due to a simple detergent-like effect but due to a specific action on the plasma membrane. The inhibitory effect of STL on protein kinase activity was through increasing GM3, but MEL had a direct inhibitory effect.
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PMID:Differentiation of human promyelocytic leukemia cell line HL60 by microbial extracellular glycolipids. 907 63

The biological activities of 7 microbial extracellular glycolipids including mannosylerythritol lipid (MEL)-A, MEL-B, polyol lipid (PL), rhamnolipid (RL), sophorose lipid (SL), succinoyl trehalose lipid (STL)-1, and STL-3 were investigated. All glycolipids except for RL were found to induce cell differentiation instead of cell proliferation in the human promyelocytic leukemia cell line HL60. To identify the differentiation direction of the induced cells, the leukocyte esterase activities were cytologically investigated, and the results showed that MEL-A, MEL-B, and PL induced HL60 to differentiate into granulocytes, while SL, STL-1, and STL-3 induced differentiation into monocytes. The 6 effective glycolipids also increased nitroblue tetrazolium (NBT) reducing ability, which is a common differentiation-associated characteristic in monocytes and granulocytes. Furthermore, it was also observed that these 6 glycolipids inhibited the activity of phospholipid- and Ca(2+)-dependent protein kinase. Additionally, the 6 effective glycolipids also induced the human myelogenous leukemia cell line K562 and the human basophilic leukemia cell line KU812 to differentiate into monocytes, granulocytes, and megakaryocytes.
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PMID:Microbial extracellular glycolipid induction of differentiation and inhibition of the protein kinase C activity of human promyelocytic leukemia cell line HL60. 914 19

Release of mitochondrial cytochrome c has been recently linked to the activation of the "executioner" phase of the cellular programs for death by apoptosis. This release is known to be negatively regulated by Bcl-2 and Bcl-XL proteins. We show here that treatment of human leukemia cells HL60 with 1,25-dihydroxyvitamin D3 (1,25D3) results in progressive increases in the levels of cellular antiapoptotic protein Mcl-1, a transient increase in Al protein level, but no increases in Bcl-2 or Bcl-XL proteins. The increase in Mcl-1 protein levels correlates with a reduced extent of apoptotic cell death induced by etoposide or the calcium ionophore A23187. The Mcl-1 protein is primarily localized in the mitochondria, and etoposide- or A23187-induced cytochrome c release is reduced in cells in which the mitochondria contain the Mcl-1 protein demonstrable by immunoblots. Raf-1 protein can also be detected in the mitochondrial fractions that contain Mcl-1 protein but not in the Mcl-1-negative fractions. These findings suggest that in these promyelocytic leukemia cells Mcl-1 has a function analogous to that of Bcl-2 in other cells, i.e., to target Raf-1 to mitochondria and to reduce cell damage-induced release of mitochondrial cytochrome c. Our findings provide a potential mechanism for the antiapoptotic action of 1,25D3 and show that differentiation and apoptosis signaling pathways not only interact but involve a proliferation-associated gene, Raf-1.
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PMID:Antiapoptotic action of 1,25-dihydroxyvitamin D3 is associated with increased mitochondrial MCL-1 and RAF-1 proteins and reduced release of cytochrome c. 928 70

The hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] promotes differentiation of a number of cell types including HL-60 promyelocytic leukemia cells. It is now established that protein kinase Cbeta (PKCbeta) plays a critical role in HL-60 cell maturation to a monocyte/macrophage phenotype. In the present study, we investigated the importance of PKCbeta levels and activation in 1,25-(OH)2D3-mediated differentiation of HL-60 cells. Cell differentiation promoted by 1,25-(OH)2D3 at 48 hr was 39 +/- 3% (mean +/- SEM) nitroblue tetrazolium (NBT) positive and at 72 hr it was 35 +/- 2% NBT positive and 70% CD14 positive. Thus, promotion of cell differentiation by 20 nM 1,25-(OH)2D3 treatment was maximal at 48-72 hr. When PKCbeta levels and cell differentiation were assayed at 72 hr, treatment with 20 nM 1,25-(OH)2D3 for the initial 6 hr increased PKCbeta levels by 175% but had little effect on cell differentiation (7 +/- 2% NBT positive; 11% CD14 positive). The effect of ionomycin, a calcium ionophore, on PKCbeta levels and cell differentiation also was examined. Alone, 5 microM ionomycin promoted few cells (3% CD14 positive) to differentiate. In contrast, cells treated with 5 microM ionomycin for 66 hr after a 6-hr pretreatment with 20 nM 1,25-(OH)2D3 resulted in 34 +/- 5% NBT positive cells and 73% CD14 positive cells. Quantitatively, this induction of differentiation was identical to that observed in cultures continuously treated with 1,25-(OH)2D3 (35 +/- 2% NBT positive; 70% CD14 positive). Therefore, ionomycin seemed to replace the requirement for the continuous presence of 1,25-(OH)2D3. Chelerythrine chloride (3 microM), a specific PKC inhibitor, blocked differentiation promoted by 1,25-(OH)2D3 alone (82 +/- 2% inhibition) or in sequence with ionomycin (86 +/- 3% inhibition). Taken together, our data show that the capacity of 1,25-(OH)2D3 to both increase PKCbeta levels and activate PKC is utilized to promote HL-60 cell differentiation. These data further suggest that 1,25-(OH)2D3 has a genomic action to increase PKCbeta levels and also a nongenomic action requiring its continuous presence to promote HL-60 cell differentiation.
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PMID:Promotion of HL-60 cell differentiation by 1,25-dihydroxyvitamin D3 regulation of protein kinase C levels and activity. 935 91

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) in addition to its classical role in calcium homeostasis regulates cell differentiation. The mechanisms involved in mediating numerous functions of 1,25(OH)2D3 are not clearly understood. In addition to genomic actions involving nuclear vitamin D receptor (VDR), some rapid nongenomic responses have been observed, but the full signalling pathway activated by 1,25(OH)2D3 has still not been described. Our recent data allow for better understanding of nongenomic effects evoked by 1,25(OH)2D3. In this paper we show that mitogen activated protein kinase (MAPK) is activated in HL-60 promyelocytic leukemia cells and in normal human keratinocytes under exposure to differentiation inducing concentrations of 1,25(OH)2D3. The MAPK is then transported to the cell nucleus in active form, which is different from the activation evoked by fetal calf serum. Experiments utilising tyrosine kinase inhibitor suggested that the postulated putative membrane vitamin D receptor, if it exists, does not have tyrosine kinase activity. Usage of protein kinase C (PKC) inhibitor allowed to state that PKC is an upstream element in the MAPK signalling pathway.
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PMID:1,25-Dihydroxyvitamin D3 induced activation and subsequent nuclear translocation of MAPK is upstream regulated by PKC in HL-60 cells. 942 86

Previously we reported that phorbol ester, a protein kinase C (PKC) activator, exhibits a unique pattern of potentiation of nitric oxide (NO)-related apoptosis in HL-60 human promyelocytic leukemia cells. Here we show that elevation of intracellular cAMP could protect HL-60 cells from NO- or NO plus PMA-induced DNA damage. Exposure of cells to sodium nitroprusside (SNP; 0.5 to 4 mM), a NO-generating agent, induced apoptotic cell death as monitored by morphological means, gel electrophoresis, and in situ TdT-apoptosis assay. However, concomitant incubation of the cells with DB-cAMP markedly inhibited SNP-induced apoptotic cell death in a dose-dependent manner. Similar results were obtained with other commonly used cAMP analogs such as CPT-cAMP and 8-C1-cAMP and the intracellular cAMP-elevating agent such as forskolin. In contrast, pretreatment of HL-60 cells with H89 or KT5720, which are known to inhibit cAMP-dependent protein kinase (PKA), abolished the protective effect of cAMP analogs and forskolin on SNP-induced apoptosis. Synergism between SNP and phorbol ester to induce apoptosis was also inhibited by prior treatment of HL-60 cells with DB-cAMP or forskolin. The effect of DB-cAMP in maintaining cell viability was not associated with the onset of G0/G1 cell cycle arrest. In addition, neither dimethyl sulfoxide nor retinoic acid (which produce granulocyte differentiation) could produce cAMP effect. Under the same conditions, DB-cAMP also inhibited NO- or NO plus phorbol ester-induced apoptosis in another transformed cell line, U-937 cells. Taken together, these findings suggest that exposure of HL-60 cells to cAMP analogs renders them more resistant to NO-induced DNA damage and further suggest the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
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PMID:Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis in human leukemic HL-60 cells. 957 15


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