Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The leukemogenic tyrosine kinase fusion protein Bcr-Abl activates a Ras-dependent pathway required for transformation. To examine subsequent signal transduction events we measured the effect of Bcr-Abl on two mitogen-activated protein kinase (MAPK) cascades--the extracellular signal-regulated kinase (ERK) pathway and the Jun N-terminal kinase (JNK) pathway. We find that Bcr-Abl primarily activates JNK in fibroblasts and hematopoietic cells. Bcr-Abl enhances JNK function as measured by transcription from Jun responsive promoters and requires Ras, MEK kinase (MAPK/ERK kinase kinase), and JNK to do so. Dominant-negative mutants of c-Jun, which inhibit the endpoint of the JNK pathway, impair Bcr-Abl transforming activity. These findings implicate the JNK pathway in transformation by a human leukemia oncogene.
 ...
PMID:The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. 852 41

We have examined whether activation of MAP kinases [or extracellular signal-regulated kinases (ERKs)] is required for the survival of rat sympathetic neurons by comparing the actions of three survival factors whose survival-promoting actions can be blocked by neutralizing Fab fragments to p21 ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344-350), nerve growth factor (NGF), the cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival was accompanied by an intense (15- to 30-fold) and steady (> 24 h) activation of p44 and p42 ERKs which waned rapidly (t1/2 approximately 30 min) upon NGF withdrawal. However, concentrations of NGF that induced a weak (4- to 5-fold) stimulation of the ERKs were not sufficient to maintain long-term survival. Moreover, prolonged and intense stimulation of the ERKs by NGF for up to 15.5 h was unable to confer long-term survival, since withdrawal of NGF after this time resulted in neuronal death that was kinetically indistinguishable from the death of neurons that had not been exposed to NGF. By contrast, CNTF and LIF continued to support survival for up to 3 days after eliciting only transient (< 30 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTcAMP induced survival for several days without any measurable activation of the ERKs. Taken together, these data suggest that ERK activation per se is neither necessary nor sufficient for survival and that alternative pathways exist for effecting long-term survival of rat sympathetic neurons.
 ...
PMID:Activation of p44 and p42 MAP kinases is not essential for the survival of rat sympathetic neurons. 854 72

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.
 ...
PMID:Extracellular signal-regulated kinase (ERK) activity is required for TPA-mediated inhibition of drug-induced apoptosis. 953 20

Retinoic acid (RA) activated the extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein kinase (MAPK) of HL-60 human myeloblastic leukemia cells before causing myeloid differentiation and cell cycle arrest associated with hypophosphorylation of the retinoblastoma (RB) tumor suppressor protein. ERK2 activation by mitogen-activated protein/ERK kinase (MEK) was necessary for RA-induced differentiation in studies using PD98059 to block MEK phosphorylation. G0 growth arrest and RB tumor suppressor protein hypophosphorylation (which is typically associated with induced differentiation and G0 arrest), two putatively RB-regulated processes, also depended on ERK2 activation by MEK. Activation of ERK2 by RA occurred within hours and persisted until the onset of RB hypophosphorylation, differentiation, and arrest. ERK2 activation was probably needed early, because delaying the addition of PD98059 relative to that of RA restored most of the RA-induced cellular response. In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation. This is consistent with the need for a nuclear retinoid receptor function in RA-induced ERK2 activation. RA reduced the amount of unphosphorylated RAR-alpha, whose activation is necessary for RA-induced differentiation and arrest. This shifted the ratio of phosphorylated:unphosphorylated RAR-alpha to predominantly the phosphorylated form. Unlike other steroid thyroid hormone receptors susceptible to phosphorylation and activation by MAPKs, RAR-alpha was not phosphorylated by the activated ERK2 MAPK. The results thus show that RA augments MEK-dependent ERK2 activation that is needed for subsequent RB hypophosphorylation, cell differentiation, and G0 arrest. The process seems to be nuclear receptor dependent and an early seminal component of RA signaling causing differentiation and growth arrest.
 ...
PMID:Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. 967 85

Members of both the mitogen activated protein (MAP) kinase and BCL2 gene families, acting in concert with other gene products, are involved in the regulation of cell viability. However, the relationship between these families, and the signal transduction networks that control viability-regulating genes, are only beginning to be elucidated. MCL1 is a viability-promoting member of the BCL2 family that exhibits a rapid increase in expression in response to specific differentiation- and apoptosis-inducing stimuli. The signal transduction pathway involved in eliciting this increase has now been investigated. In the ML-1 human myeloblastic leukemia cell line, a rapid and sustained increase in phosphorylation of the extracellular signal-regulated kinase (ERK) members of the MAP kinase family was found to precede the increase in MCL1 expression produced by 12-O-tetradecanoylphorbol 13-acetate (TPA) or the microtubule-disrupting agents colchicine and vinblastine. ERK activation was necessary for the increase in MCL1, as inhibition of the increase in ERK phosphorylation (with the inhibitor PD 98059) prevented the increase in MCL1 expression and caused rapid cell death by apoptosis. In addition, other agents that markedly increased ERK phosphorylation (lipopolysaccharide, okadaic acid) also increased MCL1 expression. In contrast, agents that did not have this marked effect did not increase MCL1. Upstream components in this ERK-mediated pathway were also identified, where the pathway was found to be stimulated by microtubule disruption acting through protein kinase C (PKC). These results indicate that expression of the MCL1 viability-enhancing gene is regulated through a cytoskeletal disruption-induced ERK-mediated signal transduction pathway. They therefore suggest a mechanism through which the cytoskeleton and MAP kinases can exert effects on cell viability.
 ...
PMID:Expression of the antiapoptotic MCL1 gene product is regulated by a mitogen activated protein kinase-mediated pathway triggered through microtubule disruption and protein kinase C. 977 65

Antigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2H3 cells induced activation of c-Jun N-terminal kinase (JNK) within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The Ag-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin (10-100 nM) and LY 294002 (100 microM) but not by the protein kinase C inhibitors calphostin C (1 and 3 microM) and Ro 31-8425 (1 and 3 microM). Pretreatment with dexamethasone (10 and 100 nM) for 18 h inhibited the Ag-induced increase in JNK activity in a concentration-dependent manner. At least 6 h of preincubation with dexamethasone was necessary to inhibit the Ag-induced JNK activation. The phosphorylation of c-Jun induced by the Ag stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The Ag-induced activation of the JNK kinase kinase mitogen-activated protein kinase-extracellular signal-regulated kinase kinase-1 was also inhibited by pretreatment with dexamethasone at 10 and 100 nM. These findings indicate that dexamethasone reduces JNK protein level and inhibits the Ag-induced activation of JNK resulting in the inhibition of c-Jun phosphorylation.
 ...
PMID:Inhibition by dexamethasone of antigen-induced c-Jun N-terminal kinase activation in rat basophilic leukemia cells. 979 29

We investigated tyrosine phosphorylation of proteins in primary human leukemia cells stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), tumor necrosis factor (TNF), thrombopoietin (TPO) and phorbol myristate acetate (PMA) in 61 patients with acute myeloid leukemia (AML), nine patients with chronic myeloid leukemia (CML) in blastic crisis and four patients in chronic phase, and compared these data of leukemia with those of normal human immature hematopoietic cells. These cytokines and PMA induced tyrosine phosphorylation of proteins in a manner characteristic for each cytokine or PMA in AML cells. G-CSF, GM-CSF and IL-3 frequently phosphorylated p92, p80, p70, p44 and p42. p95 was frequently phosphorylated by G-CSF, and was phosphorylated in one third of the cases by TPO. On the other hand, TNF selectively induced tyrosine phosphorylation of p42, and PMA selectively induced that of p44 and p42. In marked contrast to AML cells, CML cells responded poorly to cytokines with protein tyrosine phosphorylation, and normal human bone marrow mononuclear cells and CD34-positive cells also showed poor response to cytokines. The results of the immunoprecipitation studies showed tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5 induced by G-CSF, GM-CSF, IL-3 and/or TPO in six cases, that of extracellular signal-regulated kinase (ERK) by GM-CSF in two cases and that of p38 by TNF in three cases. Intracellular amount of Stat5 was markedly increased in AML cells compared with that in CML cells and normal human bone marrow cells. whereas intracellular amount of ERK and p38 was uniformly abundant in both leukemic and normal cells. These results show cytokine-specific and amplified tyrosine phosphorylation of proteins in AML cells and suggest that amplified response might, at least in part, result from the increased amount of signaling molecules such as Stat5.
 ...
PMID:Tyrosine phosphorylation of proteins in primary human myeloid leukemia cells stimulated by cytokines: analysis of the frequency of phosphorylation, and partial identification and semi-quantification of signaling molecules. 988 38

In the present study we examined in more detail the dual role of the c-JUN N-terminal kinase (JNK) and p38 stress-activated protein kinase pathways in mediating apoptosis or cellular activation in hematopoietic cells. Growth factor deprivation of the erythroleukemic cell line TF-1 led to apoptosis which was associated with an enhanced activity of JNK and p38 and immediate dephosphorylation of the extracellular signal-regulated kinases (ERKs). Enhanced activity of p38 and JNK was not only observed during apoptosis but also in TF-1 cells stimulated with IL-1. IL-1 rescued TF-1 cells from apoptosis. In this case, the upregulation of p38 and JNK was associated with an enhanced activity of ERK. By using SB203580, a specific inhibitor of the p38 signaling pathway, it was demonstrated that p38 plays a pivotal role in the apoptotic process. SB203580 repressed the apoptotic process to a large extent. In contrast, PD98059, a specific inhibitor of the ERK pathway, counteracted the suppressive effects of SB203580 and IL-1 on the apoptotic process indicating that the protective effect of SB203580 and IL-1 might be the result of a shift in the balance between the ERK1/2 and p38/JNK route. This was also supported by experiments with TF-1 cells overexpressing the Shc protein that demonstrated a significantly lower percentage of apoptotic cells, which coincided with higher ERK activity. Finally, the IL-1 and SB203580-mediated effects were associated with an enhanced nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) binding activity, which could also be blocked by PD98059. These data demonstrate a dual function of the p38 pathway whereby other factors, such as ERK kinases, AP-1 and NF-kappaB, might determine the final cellular response.
Leukemia 1999 Jul
PMID:A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation. 1040 Apr 19

Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
 ...
PMID:ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. 1071 38

The purpose of this study was to evaluate whether the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) signaling pathway contributes to 12-O-tertadecanoyl phorbol 13-acetate (TPA)-mediated protection from taxol-induced apoptosis of human leukemia HL-60 cells. Treatment of cells with taxol for 12 h resulted in apoptosis of HL-60 cells. TPA was protective against taxol-induced apoptosis and this anti-apoptotic effect was reversible when TPA was used in conjunction with staurosporine and H-7, PKC inhibitors, suggesting that TPA may protect HL-60 cells against taxol-induced apoptosis via the PKC-dependent pathway. Since TPA stimulates MEK signal transduction pathway in HL-60 cells, we postulated that MEK pathway may be playing a role in the ability of TPA to inhibit taxol-induced apoptosis. PD098059, a specific MEK kinase inhibitor, abolished the ability of TPA to inhibit taxol-induced apoptosis. These results suggest that activation of PKC in HL-60 cells confers protection against taxol-induced apoptosis and that MEK mediates anti-apoptotic signaling of PKC.
 ...
PMID:12-O-tetradecanoyl phorbol 13-acetate, protein kinase C (PKC) activator, protects human leukemia HL-60 cells from taxol-induced apoptosis: possible role for extracellular signal-regulated kinase. 1073 57


1 2 3 4 5 6 7 8 9 10 Next >>