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: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-lapachone (beta-Lap) has been found to inhibit DNA topoisomerases (Topos) by a mechanism distinct from that of other commonly known Topo inhibitors. Here, we demonstrated a pronounced elevation of H2O2 and O2- in human leukemia HL-60 cells treated with beta-Lap. Treatment with other Topo poisons, such as camptothecin (CPT), Vbeta-16, and GL331, did not have the same effect. On the other hand, antioxidant vitamin C (Vit C) treatment effectively antagonized beta-Lap-induced apoptosis. This suggested that a reactive oxygen species (ROS)-related pathway was involved in beta-Lap-induced apoptosis program. We also found that c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 was persistently activated in apoptosis induced by beta-Lap. Overexpression of a dominant-negative mutant mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide or Vit C all prevented beta-Lap-induced JNK activation and the subsequent apoptosis. Only the expression of MEKK1-DN, not Vit C treatment, blocked the JNK activity induced by CPT, Vbeta-16, or GL331. These results confirm again that ROS acts as a mediator for JNK activation during beta-Lap-induced apoptosis. Furthermore, we found that beta-Lap can stimulate CPP32/Yama activity, which was, however, markedly inhibited by the MEKK1-DN expression or Vit C treatment. Again, CPT-induced CPP32/Yama activation can be abolished by MEKK1-DN but not by Vit C treatment. Taken together, these results indicate that beta-Lap but not other Topo inhibitors triggers apoptosis signaling, i.e., JNK and subsequent CPP32/Yama activation are mediated by the generation of ROS.
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PMID:Activation of c-Jun NH2-terminal kinase and subsequent CPP32/Yama during topoisomerase inhibitor beta-lapachone-induced apoptosis through an oxidation-dependent pathway. 992 52

Bufalin, a component of the Chinese medicine chan'su, induces apoptosis in various lines of human tumor cells, such as leukemia HL60 and U937 cells, by altering the expression of apoptosis-related genes, for example, bcl-2 and c-myc. In this study, we characterized a gene that is involved in bufalin-induced apoptosis by the differential display (DD) technique. The partial nucleotide sequence of one of the differentially expressed clones obtained after treatment with bufalin was identical to that of the human gene for Tiam1. When U937 cells were treated with 10(-7) M bufalin, expression of both Tiam1 mRNA and the protein was induced 1 h after the start of the treatment. The increase of Tiam1 mRNA was transient but the level of Tiam1 protein continued to increase at least for 6 h. In addition, the activities of Rac1 and p21-activated kinase (PAK) were also stimulated by bufalin treatment. To evaluate the role of Tiam1 in the apoptotic process, we examined the effects of the expression of sense and antisense RNA for Tiam1 in U937 cells. Apoptosis was strongly induced by bufalin in cells that expressed sense RNA for Tiam1 as compared to apoptosis in control cells treated with bufalin only. Cells expressing antisense RNA for Tiaml were significantly more resistant than the control bufalin-treated cells to induction of DNA fragmentation in response to bufalin. Moreover, sense transformants had elevated activities of PAK and c-Jun NH2-terminal kinase (JNK). These results suggest that Tiaml might play a critical role in bufalin-induced apoptosis through the activation of Rac1, PAK, and JNK pathway.
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PMID:Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells. 1022 92

Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that induce apoptotic cell death in a variety of tumor cell lines. Although their precise mechanism of action is unknown, ALPs primarily act on the cell membrane, where they inhibit signaling through the mitogen-activated protein kinase (MAPK) pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis in certain cell types, we tested the effect of ALPs in combination with ionizing radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis in the human leukemia cell lines U937 and Jurkat T but not in normal vascular endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance the induction of apoptosis in both leukemic cell lines. All tested ALPs not only prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP-induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data support the view that ALPs and ionizing radiation cause an enhanced apoptotic effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and the apoptotic SAPK/JNK pathways. This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies.
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PMID:Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. 1034 58

We recently demonstrated that physiological induction of apoptosis by cytotoxic sphingolipid messengers proceeds via activating protein-1 (AP1)-dependent and AP1-independent mechanisms in U937 human monoblastic leukemia cells. Here we examine involvement of the stress-activated protein kinase (SAPK) cascade and AP1 in the initiation of apoptosis in U937 cells by podophyllotoxin-derived inhibitors of topoisomerase II. Induction of apoptotic cell death and DNA damage by treatment of U937 cells with etoposide (100 microM) was associated with phosphorylation and activation of the c-Jun NH(2)-terminal kinase (JNK1) SAPK enzymes p46 and p54-JNK2 and transient increases in expression of the transcription factor c-Jun, a primary JNK substrate. These responses were accompanied by a modest, but sustained, recruitment of the mitogen-activated protein kinases p42-extracellular signal receptor-activated kinase (ERK)1 and p44-extracellular signal receptor-activated kinase 2. The capacity of etoposide to promote double-stranded DNA degradation and cell death was unaffected by manipulations that interfere with SAPK signaling outflow through c-Jun/AP1, including: 1) pharmacological inhibition of AP1 activity by diferuloylmethane and 2) molecular ablation of normal c-Jun function by the Jun dominant-negative mutant TAM-67. Cytotoxicity of the structurally related compound teniposide was similarly unaffected. In parallel trials, the lethal actions of ceramide (but not of sphingosine) were markedly diminished by pretreatment with diferuloylmethane or expression of TAM-67, confirming the effectiveness of these interventions in suppression of SAPK/AP1-dependent apoptosis. The involvement of AP1 in the proapoptotic actions of other inhibitors of topoisomerase II activity was also evaluated. Induction of cell death by the anthracyclines daunorubicin, daunorubicin, and idarubicin was found to be insensitive to pretreatment with diferuloylmethane or expression of TAM-67. Collectively, the present data indicate that induction of apoptosis by etoposide and related inhibitors of topoisomerase II is mediated through a cell death pathway that does not require SAPK-dependent recruitment of AP1. These findings additionally suggest that activation of the SAPK represents a consequence, rather than an underlying cause, of etoposide-induced apoptosis in myeloid leukemia cells.
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PMID:Evidence that the apoptotic actions of etoposide are independent of c-Jun/activating protein-1-mediated transregulation. 1045 18

Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH2-terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, differentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These findings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.
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PMID:Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis. 1049 71

Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
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PMID:Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. 1059 2

JEM-1 is a novel gene whose mRNA expression in acute promyelocytic leukemia (APL) is induced by retinoid treatments. The gene product, a 45 kDa basic nuclear factor containing a leucine repeat, was transiently expressed in HeLa or COS-7 cells and immunocharacterized within the nuclei in fine punctuated structures which increase in size after cell transfection. Jem-1 was not expressed in the nucleoli. Experimental deletion of peptide domains of Jem-1 (JemDelta331-400 and Jem DeltaL179-206) showed that its C-terminal sequence (Thr331 --> Leu400) is required for nuclear translocation, while the leucine repeat domain (Arg179 --> Glu206) has no influence on subcellular localization. The Jem-1 protein was not detected in the PML-containing nuclear bodies or in speckled structures containing the splicing factor SC-35. In contrast it was localized in the nucleus in structures containing activator protein-1 (AP-1). DNA mobility shift assays showed that the in vitro translated Jem protein interacts neither with the DNA binding site of AP-1, nor directly with in vitro co-translated c-Fos or/and c-Jun proteins bound to this specific sequence. Interestingly, Jem-1-1 increased substantially the transcriptional activity of c-Jun (three-fold) and more strongly that of ectopically co-expressed c-Fos and c-Jun (five- to six-fold), as measured by a CAT reporter gene driven by a heterologous promoter containing the AP-1 binding site of the human collagenase gene. These synergistic effects were strongly Jem-1 dose-dependent. However, Jem-1 alone showed no activity on the collagenase promoter. A deletion of the leucine repeat of Jem-1 (Arg179 --> Glu206) did not diminish the enhancer capacity of Jem-1 on AP-1 activity. In contrast, the enhanced AP-1 activity was abrogated when Jem-1 was deleted of its C-terminus (Thr331 --> Leu400). We conclude that the 45 kDa nuclear product of the JEM-1 gene has features of a novel transcription cofactor, which is enhancing AP-1 activity without directly interacting with c-Jun or c-Fos proteins. Possible implications of these findings for APL cell maturation are discussed.
Leukemia 1999 Dec
PMID:JEM-1, a novel nuclear co-factor: localisation and functional interaction with AP-1. 1060 19

We found that antitumor drugs such as cytotrienin A, camptothecin, taxol, and 5-fluorouracil induced the activation of a 36-kDa protein kinase (p36 myelin basic protein (MBP) kinase) during apoptosis in human promyelocytic leukemia HL-60 cells. This p36 MBP kinase, which phosphorylates MBP in an in-gel kinase assay, results from the caspase-3-mediated proteolytic cleavage of MST/Krs protein, a mammalian Ste20-like serine/threonine kinase. Herein the correlation between cytotrienin A-induced apoptosis and the activation of MST/Krs proteins was examined in human tumor cell lines, including leukemia-, lung-, epidermoid-, cervix-, stomach-, and brain-derived cell lines. In cytotrienin A-sensitive cell lines, we observed a strong activation of p36 MBP kinase by cleavage of the C-terminal regulatory domain of full-length MST/Krs proteins by caspase-3. When the kinase-inactive mutant form of MST/Krs protein was overexpressed in cytotrienin A-sensitive HL-60 cells, the cytotrienin A-induced apoptosis was partially inhibited. Because cytotrienin A also activated c-Jun N-terminal kinase, we examined the effect of the expression of dominant negative c-Jun on cytotrienin A-induced apoptosis. The expression of dominant negative c-Jun also partially inhibited cytotrienin A-induced apoptosis. Furthermore, coexpression of kinase-inactive MST/Krs protein and dominant negative c-Jun completely suppressed cytotrienin A-induced apoptosis. These findings suggest that the proteolytic activation of MST/Krs and c-Jun N-terminal kinase activation are involved in cytotrienin A-induced apoptosis in human tumor cell lines.
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PMID:Activation of MST/Krs and c-Jun N-terminal kinases by different signaling pathways during cytotrienin A-induced apoptosis. 1072 20

Human T-cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL). This study examined the status of the oncogenic transcription factor AP-1 in leukemic cells freshly isolated from patients with ATL. Leukemic cells from peripheral blood of all patients with ATL exhibited constitutive AP-1 DNA binding activity, whereas mononuclear cells from normal individuals did not. In agreement with previous studies, HTLV-I transforming protein, Tax, was found to stimulate the DNA binding activity of AP-1 in a T-cell line. However, HTLV-I genes, including Tax, were not significantly expressed in leukemic cells freshly obtained from patients with ATL. Moreover, all T-cell lines derived from leukemic cells of patients with ATL also displayed constitutive AP-1 DNA binding activity, but expressed little Tax protein. Thus, leukemic cells of patients with ATL appear to have Tax-independent mechanisms that induce AP-1 activity, both in vivo and in vitro. In antibody supershift experiments, AP-1 in fresh leukemic cells and ATL-derived cell lines were found to contain JunD. Consistently, all primary ATL cells and ATL-derived cell lines expressed high levels of JunD messenger RNA. Our results suggest that AP-1 is activated in leukemic cells of patients with ATL through a Tax-independent mechanism and this may play a role in the deregulated phenotypes of ATL leukemic cells. (Blood. 2000;95:3915-3921)
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PMID:Constitutive activation of transcription factor AP-1 in primary adult T-cell leukemia cells. 1084 28

Treatment of leukemic cells with phorbol 12-myristate 13-acetate (PMA) induces a short-lived phosphorylation and activation of stress-activated protein kinase (SAPK) and cellular differentiation. To investigate whether the rapid deactivation of SAPK results from dephosphorylation by dual-specificity phosphatases (DSPs), we studied regulation of the DSP hVH5 and its murine orthologue M3/6 in K562 human leukemia cells. PMA treatment rapidly induced hVH5 transcripts in these cells, and induced expression of M3/6 completely inhibited PMA-stimulated phosphorylation of SAPK, suggesting a feedback loop to control SAPK activity. Using both stable cell lines and transient transfection we demonstrate that activation of SAPK rapidly stimulated phosphorylation of M3/6. This phosphorylation did not regulate the half-life of total cellular M3/6. hVH5 and M3/6 shares with all sequenced mammalian DSPs an amino acid motif, XILPXLXL, located approximately 80 amino acids from the active site. The hVH5-M3/6 sequence, RILPHLYL, shares significant homology with the SAPK binding site of the c-Jun protein, called the delta domain. This motif was found to be important for DSP function, because deletion of RILPHLYL inhibits SAPK-mediated phosphorylation of M3/6, and deletion of this sequence or mutation of the LYL portion blocks the ability of this phosphatase to dephosphorylate SAPK.
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PMID:Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. Analysis of a delta-like domain. 1091 87


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