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)

HL60 cells are human promyeloid cells that can be induced to differentiate by physiological stimuli (e.g. all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 (D3), granulocyte colony-stimulating factor (G-CSF)) and by non-physiological agents such as dimethysulphoxide (DMSO) and protein kinase C-activating phorbol esters. The sensitivity of HL60 cells to physiological differentiating agents, but not to DMSO, is enhanced when cells are exposed to 'anti-inflammatory agents' (e.g. indomethacin) or are 'primed' (pretreated) with a small amount of ATRA: alone, neither treatment induces differentiation. We earlier suggested that indomethacin might act by inhibiting the endogenous formation of a differentiation-suppressing prostanoid (Bunce, C.M., et al. (1994) Leukemia 8, 595-604). Studies of the formation of prostanoids by HL60 cells and of the effects of prostanoids on these cells failed to identify any prostanoid that could be implicated in sensitization by indomethacin. 3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) is another target of such 'anti-inflammatory agents'. Steroid inhibitors of 3 alpha-HSD sensitized HL60 cells to inducers of differentiation in a manner similar to indomethacin. 3 alpha-HSD is a member of the aldoketoreductase enzyme family, which comprises many enzymes of similar size and primary sequence. A protein that was recognised by an antiserum to 3 alpha-HSD was found in HL60 cells, but the cells showed no detectable 3 alpha-HSD activity. The 3 alpha-HSD-like protein was strikingly down-regulated by 'priming' doses of ATRA. When treatment with a differentiation-sensitizing 'anti-inflammatory agent' or steroid was combined with ATRA "priming', the effects of the different treatments were not additive: the resulting increase in sensitivity equalled that achievable by either treatment alone. We conclude that interference with a single intracellular regulatory mechanism underlies the increases in sensitivity of cells to differentiating agents that are caused by anti-inflammatory agents, by certain steroids and by 'priming' with ATRA. Decreased activity of a yet-to-be-identified member of the aldoketoreductase family of dehydrogenases is likely to be a central feature of a previously unrecognised mechanism that controls the responsiveness of cells to environmental stimuli such as retinoids and D3.
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PMID:Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family. 866 46

Based upon earlier reports of synergism in cells of lymphoid origin, we have examined interactions between the organotellurium compound AS101 and the protein kinase C (PKC) activator bryostatin 1 with respect to differentiation and Ara-C-induced apoptosis in human myeloid leukemia cells (HL-60). Although preincubation with bryostatin 1 (10 nM) for 24 h significantly increased DNA fragmentation and apoptosis in cells subsequently treated with 10 microM Ara-C for 6 h, this effect was not enhanced by co-administration of AS101 (1.5 microM). However, while exposure of cells to AS101 or bryostatin 1 alone for 72 h was ineffective in inducing cellular maturation, combined treatment resulted in the induction of differentiated features in a subset of cells, manifested by an increase in cell adherence, CD11b expression, cytoplasmic granularity and cell spreading. In addition, cells exposed to the combination of AS101 and bryostatin 1, in contrast to cells incubated with these agents individually, displayed a significant decline in the S-phase and a corresponding increase in the G0/G1 cell populations. These events were accompanied by an increase in protein expression of the cyclin-dependent kinase inhibitor, p21 (WAF1/CIP1/MDA6), and a decline in expression of the c-myc protein. AS101 failed to increase intracellular free Ca2+ ([Ca2+]i) in HL-60 cells, or reverse the profound PKC down-regulation induced by bryostatin 1. Whereas treatment of cells with 1.5 microM AS101 or 10 nM bryostatin 1 for 24 h exerted minimal growth inhibitory effects, combined exposure to these agents reduced colony formation by over 70%. Finally, although addition of AS101 did not potentiate apoptosis induced by the bryostatin 1/Ara-C combination, it did lead to a further reduction in clonogenicity. Together, these findings demonstrate that AS101 partially restores the ability of bryostatin 1 to trigger a differentiation program in an otherwise unresponsive HL-60 cell line, possibly by facilitating bryostatin 1-mediated G1 arrest. They also indicate that AS101 potentiates the antiproliferative effects of bryostatin 1 administered alone or in combination with Ara-C through a mechanism other than, or in addition to, induction of apoptosis.
Leukemia 1996 Jul
PMID:Effect of AS101 on bryostatin 1-mediated differentiation induction, cell cycle arrest, and modulation of drug-induced apoptosis in human myeloid leukemia cells. 868 95

We examined the effects of a cell-permeable ceramide analog, C2-ceramide, on the growth of TNF-alpha-resistant B lymphoma Raji cells lacking TNF-alpha-receptors (TNF-R). C2-ceramide inhibited the clonal growth of not only TNF-alpha-sensitive myeloid leukemia cells (HL60 and U937) but also Raji cells. Following stimulation with C2-ceramide, HL60 and U937 cells showed apoptotic cell death, whereas Raji cells did not show a detectable level of apoptosis. However, a cell-cycle arrest in G0/G1 phase was observed in Raji cells after the treatment with C2-ceramide, which was accompanied by the dephosphorylation of retinoblastoma (RB) gene products and decreased expression of p53 proteins. Failure of C2-ceramide to induce apoptosis in Raji cells might be explained by the lack or low expression of apoptosis-inducing proteins by two lines of evidence: (1) Raji cells were resistant to apoptosis induced by ceramide even in the presence of transcription/translation inhibitors; (2) Bax protein expression was not detectable in Raji cells, although Bcl-2 protein expression in Raji cells was even less than that in HL60 and U937 cells. Moreover, protein kinase C (PKC), whose activation has been described to inhibit ceramide-induced apoptosis, inhibitor H-7 did not induce apoptotic cell death in Raji cells, suggesting that an imbalance between PKC and ceramide pathways is not the reason for the resistance of Raji cells against ceramide-induced apoptosis. Finally, ceramide-induced activation of nuclear factor kappaB (NF-kappaB) was observed in Raji cells as well as HL60 cells, indicating that activation of this molecule may not be specific for apoptosis. By using the present model, one can dissect cell-cycle arrest and apoptosis induced by ceramide.
Leukemia 1996 Dec
PMID:Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-alpha-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. 894 36

The CD9 antigen, a major platelet glycoprotein, is a member of the tetraspan superfamily. We show that treatment of K562 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) which induces megakaryocytic differentiation, leads to a seven-fold increase in CD9 expression, which becomes associated with the integrin beta1, suggesting that it is functionally relevant. The upregulation of CD9 expression precedes the appearance of the megakaryocytic-specific marker GPIIb (CD41) as well as integrins beta3 (GPIIIa/CD61), alpha v (CD51) and VLA-2 (CD49b). Both GPIIb/IIIa expression and CD9 upregulation are dependent on protein kinase C (PKC) activation since they are blocked by the specific inhibitor GF109203X. Steady-state levels of CD9 and GPIIb mRNA were also measured by quantitative RT-PCR. Both messengers were detected on resting cells and were shown to accumulate during TPA treatment. However, the increase of the CD9 mRNA was detected much earlier than the increase of GPIIb mRNA (1-2 h vs 24-48 h). Using different constructs of the 5'-flanking domain of the CD9 gene cloned ahead of the CAT reporter gene, we could demonstrate that a responsive element was located in a 52 bp fragment of the promoter of the CD9 gene. Altogether, these data suggest that CD9 upregulation in the megakaryocytic lineage could occur at early stages of differentiation.
Leukemia 1997 Aug
PMID:Upregulation of CD9 expression during TPA treatment of K562 cells. 926 83

The transcription factor NF-kappaB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-kappaB has IkappaB-like properties by sequestering the p65 transactivating subunit in the cytosol of cells. In transient transfection assays we demonstrated that p100 has an inhibitory effect on the NF-kappaB-dependent IL-6 promoter activity. In view of this finding, we studied the regulation of the p100 subunit in human monocytes in response to LPS, the inflammatory cytokines IL-1beta and TNF-alpha and lymphokines. The results demonstrate that LPS, IL-1beta, and TNF-alpha induce p100 expression at mRNA and protein level while IFN-gamma, IL-3 and IL-4/IL-10 have no effect. The induction of p100 expression was shown to be mediated by a two-fold increase in the p100 transcription rate and a two-fold increase in p100 mRNA stability. Furthermore the p100 mediated upregulation was dependent on a tyrosine kinase dependent pathway rather than the protein kinase C pathway. NF-kappaB is a complex of either p50 homodimers or a p50/p65 heterodimer. The latter is known to strongly autoregulate p100 transcription. We therefore examined the composition of NF-kappaB induced by LPS vs the different lymphokines. LPS-induced NF-kappaB showed a distinct p65 supershift whereas the composition of NF-kappaB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-kappaB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-kappaB predominantly consisting of p50 homodimers.
Leukemia 1998 Mar
PMID:Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines. 952 31

Leukemia cells respond to toxic stimuli by undergoing a form of programmed cell death known as apoptosis. However, the signaling events responsible for the execution of this form of death are poorly understood. Mitogen-activated protein kinase (MAPK) signaling cascades are involved in the cellular response to extracellular stimuli. Specifically, extracellular signal-regulated kinases (ERKs) have been associated with proliferation and differentiation, whereas the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs) have been implicated in cell arrest and death. We report the use of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the inhibition of apoptosis in HL-60 cells stimulated with the JNK/SAPK activator anisomycin. This anti-apoptotic effect was accompanied by a sustained increase in ERK activity. Furthermore, the use of protein kinase C (PKC) inhibitors suggested that PKC was involved in the induction of ERK activity and in the inhibition of apoptosis by TPA since the inhibition of apoptosis was attenuated when cells were pretreated with PKC inhibitors. Lastly, we observed that the use of the MEK1 inhibitor PD98059 inhibited TPA-mediated ERK activity and abrogated the anti-apoptotic effects of TPA. However, apoptotic inhibition was not solely ERK-dependent since cells lacking JNK/SAPK stimulation did not undergo apoptosis. Therefore, we conclude that TPA inhibits the induction of apoptosis in anisomycin-treated HL-60 cells through an ERK-dependent pathway and that this effect can be reversed by the attenuation of ERK activity accompanied with the stimulation of JNK/SAPK activity.
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PMID:Extracellular signal-regulated kinase (ERK) activity is required for TPA-mediated inhibition of drug-induced apoptosis. 953 20

We have analyzed the differentiation program of growth factor-dependent TF-1 erythroleukemia cells as well as clones with inducible expression of the APL-specific PML/RARalpha protein. We have shown that TF-1 cells may be induced to megakaryocytic differentiation by phorbol ester (phorbol dibutyrate, PDB) addition, particularly when combined with thrombopoietin (Tpo). RT-PCR studies showed that Tpo induces Tpo receptor (TpoR or c-mpl), whose expression was further potentiated by PDB addition. When the cells are induced with both PDB and Tpo erythropoietin receptor (EpoR) expression was inhibited. In the absence of Zn2+-induced PML/RARalpha expression, PDB and Tpo induced megakaryocytic differentiation of TF-1 MTPR clones as observed in 'wild-type' TF-1 cells. Conversely, when PML/RARalpha expression was induced by Zn2+, PDB and Tpo treatment of these clones caused only a reduced level of megakaryocytic differentiation. These observations indicate that: (1) TF-1 cells as well as other erythroleukemic cells, possess the capacity to differentiate to megakaryocytic cells when grown in the presence of protein kinase (PKC) activators and more efficiently when combined with Tpo; (2) the PML/RARalpha gene has a wide capacity to interfere with the program of hematopoietic differentiation, including megakaryocytic differentiation. Finally, we also observed that PML/RARalpha expression in TF-1 cells induces an up-modulation of interleukin-3 receptor, c-kit and c-mpl, a phenomenon which may offer these cells a growth advantage.
Leukemia 1998 Apr
PMID:Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol esters and thrombopoietin and is blocked by expression of PML/RARalpha fusion protein. 955 15

During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21(Cip-1/MDA6/WAF1). These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio- and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21(Cip-1/MDA6/WAF1) expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.
Leukemia 1998 Dec
PMID:The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity. 984 14

One of the objectives of treatment for patients with acute promyelocytic leukemia (APL) is to induce tumor cell differentiation and block cell proliferation. Acute promyelocytic leukemia cells (NB4) responded to the combination treatment of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] plus phorbol 12-myristate 13-acetate (PMA) and differentiated into monocyte/macrophage-like cells, as well as expressed strong alkaline phosphatase (ALP) activities. Since PMA has limited clinical application due to its tumor-promoting effect, another protein kinase C activator, bryostatin-1, was currently tested for its interaction with 1alpha,25(OH)2D3 to induce NB4 cell differentiation and block cell proliferation. Bryostatin-1 alone, but not 1alpha,25(OH)2D3 alone, significantly inhibited cell proliferation and induced NB4 cell differentiation into monocyte/macrophages; however neither bryostatin-1 nor 1alpha,25(OH)2D3 alone induced ALP expression. Like PMA, bryostatin-1 synergistically interacted with 1alpha,25(OH)2D3 to stimulate ALP expression 30-fold over the control (P < 0.001) and further promote appearance of monocyte/macrophage-like cells. The ALP stimulation was both time- and dose-dependent. Thus, we demonstrate for the first time that the combination of bryostatin-1 and 1alpha,25(OH)2D3 strongly affect NB4 cell differentiation and proliferation. Therefore, this proposed combination treatment may be an alternatively potential therapeutic regimen for APL patients and assay of ALP may be a more sensitive and facile way to monitor the possible remission of APL patients.
Leukemia 1999 Feb
PMID:Bryostatin-1 and 1alpha,25-dihydroxyvitamin D3 synergistically stimulate the differentiation of NB4 acute promyelocytic leukemia cells. 1002 2

The effects of the protein kinase C (PKC) activator and down-regulator bryostatin 1 were examined with respect to paclitaxel-induced apoptosis and antiproliferative activity in human myeloid leukemia cells (U937) displaying enforced expression of the anti-apoptotic protein Bcl-xL. Overexpression of Bcl-xL blocked various aspects of paclitaxel-mediated apoptosis, including caspase-3 activation, degradation of poly(ADP-ribose) polymerase (PARP), loss of mitochondrial membrane potential (Delta Psim), and release of cytochrome c. However, subsequent (but not prior) exposure of paclitaxel-treated U937/Bcl-xL cells (500 nM; 6 h) to bryostatin 1 (10 nM; 15 h) restored the extent of apoptosis, caspase activation, and mitochondrial damage to levels approximating those in paclitaxel-treated empty-vector control cells (U937/Neo). Potentiation of paclitaxel-induced apoptosis by bryostatin 1 in U937/Bcl-xL cells occurred primarily in the G2M cell population, and was associated with alterations in Bcl-xL gel mobility and a reduction in paclitaxel-mediated stimulation of CDK1 activity. Enhancement of paclitaxel-induced apoptosis by bryostatin 1 in Bcl-xL overexpressors was accompanied by a corresponding reduction in clonogenic potential. In contrast to its effects on apoptosis, bryostatin 1 failed to restore paclitaxel-mediated increases in free Bax levels in U937/Bcl-xL cells. Lastly, the actions of bryostatin 1 were mimicked by a pharmacologic inhibitor of the MEK1/MAP kinase pathway (PD98059), but not by SB203580, an inhibitor of p 38 MAP kinase. Moreover, sequential exposure of both U937/Neo or/Bcl-xL cells to paclitaxel followed by bryostatin 1 or PD98059 was associated with a net reduction in MAP kinase activity. Collectively, these findings indicate that protection against paclitaxel-mediated mitochondrial dysfunction and apoptosis in human U937 leukemia cells conferred by Bcl-xL overexpression can be substantially overcome by bryostatin 1 and possibly other agents that interrupt the MAP kinase signal transduction pathway.
Leukemia 1999 Oct
PMID:Bryostatin 1 enhances paclitaxel-induced mitochondrial dysfunction and apoptosis in human leukemia cells (U937) ectopically expressing Bcl-xL. 1051 58


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