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)

Human T cell leukemia virus type 1 (HTLV-1) Tax protein transforms primary human T cells in vitro. We previously showed that Tax induces the expression of various family members of the transcription factor AP-1 such as c-Jun, JunD, c-Fos, and Fra-1 at the mRNA level in T cells. In this study, we have examined the ability of Tax to activate transcription through the AP-1-binding site (AP-1 site). A transient transfection study showed that Tax can activate transcription through the AP-1-binding site in a human T cell line, whereas any combination of AP-1 proteins did so much less than Tax, indicating that the activation of the AP-1 site by Tax may require a mechanism other than the induction of AP-1 mRNA. Fresh peripheral blood leukemia cells of all surveyed ATL patients displayed constitutive AP-1 DNA-binding activity, whereas no normal individuals did. However, the HTLV-1 genes, including tax, are not significantly expressed in fresh leukemia cells from ATL patients. Our present results suggest that activation of AP-1 occurs through Tax-dependent and -independent mechanisms in HTLV-1-infected T cells, which may play some roles in dysregulated phenotypes of HTLV-1-infected cells.
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PMID:Activation of oncogenic transcription factor AP-1 in T cells infected with human T cell leukemia virus type 1. 1108 Jul 98

In the present study, we investigated the effects of geranylgeraniol (GGO), a potent inducer of apoptosis in various lines of human tumor cells, on signal transduction cascades involved in apoptosis in human leukemia cells. GGO strongly induced the activation of c-Jun N-terminal kinase (JNK/SAPK) within 2 h in U937 and K562 cells, while neither ERK nor p38 was activated to any considerable extent during GGO-induced apoptosis. Transient expression of a constitutively active mutant form of mitogen-activated protein kinase kinase 1 (MEKK1), deltaMEKK1, or of deltaMEKK1-green fluorescent protein (GFP) in K562 cells activated JNK, but not a caspase-3-like protease, and was insufficient to induce cell death but rendered cells susceptible to GGO-induced cell death. Stable expressions of deltaMEKK1-GFP in U937 cells gave similar results. In contrast to VP-16-induced apoptosis, GGO-induced activation of JNK was almost completely inhibited by benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD) and by benzyloxycarbonyl-Asp-CH2OC[O]-2,6,-dichlorobenzene (Z-Asp), indicating that the JNK-activation step is located downstream of the caspase signaling pathway in GGO-induced apoptosis. Moreover, apoptosis induced by GGO was significantly inhibited in two lines of cells with a dominant-negative deletion mutation in c-Jun, indicating a requirement for JNK signaling. In addition, unlike the effects on other inducers of apoptosis, the activation of JNK and of the caspase-3-like protease by GGO was significantly delayed by 12-O-tetradecanoylphorbol-13-acetate (TPA), suggesting that the site of inhibition by TPA might be located upstream of the protease and JNK in the GGO-induced apoptotic signaling pathway.
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PMID:The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs. 1108 77

Human T-cell leukemia virus type 1 (HTLV-1) Tax protein induces the expression of various family members of the transcription factor AP-1, such as c-Jun, JunD, c-Fos, and Fra-1, at the level of RNA expression in T cells. We examined the activity of Tax in transcription through AP-1-binding sites (AP-1 site) in T cells. Transient transfection studies showed that Tax activated the expression of a luciferase gene regulated by two copies of an AP-1 site in the human Jurkat T-cell line. Tax activates the expression of viral and cellular genes through two different enhancers: a cAMP-responsive (CRE)-like element and a kappaB element. Two Tax mutants differentially activated expression of these two elements. Tax703 preferentially activated the kappaB element but not the CRE-like one, whereas TaxM22 showed the reverse. In addition, Tax703 and Tax, but not TaxM22, converted cell growth of a mouse T-cell line from being interleukin (IL)-2-dependent to being IL-2-independent. Unlike the wild-type Tax, Tax703 and TaxM22 only weakly activated the AP-1 site in the T-cell line. Thus, Tax seems to activate the AP-1 site via mechanisms distinct from those of kappaB or CRE-like elements, and the activation of the AP-1 site is dispensable for IL-2-independent growth of CTLL-2. Electrophoretic mobility shift assays showed that Tax induced strong binding activity to an AP-1 site in CTLL-2, whereas Tax703 did not, indicating that the induction of binding activity to the AP-1 site is essential for the transcriptional activation by Tax. The binding complex induced by Tax in CTLL-2 contained JunD and Fra-2. Other AP-1 proteins were undetectable. Activation of transcription through the AP-1 site in Jurkat cells by JunD and/or Fra-2 was weak. c-Jun, JunB, and c-Fos activation was greater, although the level was still less than that with Tax. Thus, the induction of AP-1 mRNA by Tax may not be sufficient for a complete activation of AP-1 site by Tax. Our results suggest that Tax activates the transcription of cellular genes with AP-1 sites by inducing the DNA-binding activity of AP-1 proteins in T cells, a mechanism distinct from those of CRE-like and kappaB elements.
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PMID:Human T-cell leukemia virus type 1 tax protein activates transcription through AP-1 site by inducing DNA binding activity in T cells. 1114 87

Paclitaxel is a novel anticancer drug that has demonstrated efficacy toward treating several malignant tumor types. Here, we demonstrate that c-Jun NH(2)-terminal kinase (JNK), but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2, was persistently activated by paclitaxel or other microtubule-damaging agents within human leukemia HL-60 cells. Overexpression of a dominant-negative mutant, mitogen-activated protein kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide prevented paclitaxel-induced JNK activation, Bcl-2 phosphorylation and apoptosis. Furthermore, we found that the full-length MEKK1 was cleaved to a 91-kDa carboxyl-terminal fragment at the earlier time of apoptosis induced by microtubule-damaging agents. This cleavage, however, occurred consistently with JNK activation and Bcl-2 phosphorylation, but preceded DNA fragmentation in cells in response to paclitaxel activity. The caspase inhibitor Ac-Asp-Glu-Val-Asp-CHO (DEVD-CHO), but not Ac-Tyr-Val-Ala-Asp-CHO (Ac-YVAD-CHO), effectively blocked MEKK1 cleavage, JNK activation, Bcl-2 phosphorylation, and subsequent apoptosis. Subcellular fractionation revealed that the 91-kDa C-terminal MEKK1 fragment was translocated to cytosol. Notably, the MEKK1 fragment could be coimmunoprecipitated with anti-JNK antibodies, suggesting that a signaling complex of C-terminal MEKK1/stress-activated protein kinase/extracellular-signal regulated kinase 1/JNK formed during apoptosis induced by microtubule-damaging agents. Taken together, our results suggest that disruption of cytoarchitecture by paclitaxel triggers a novel apoptosis-signaling pathway, wherein an active DEVD-directed caspase (DEVDase) initially cleaves MEKK1to generate a proapoptotic kinase fragment that is able to activate JNK and subsequent Bcl-2 phosphorylation, finally eliciting cell death.
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PMID:Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells. 1116 Aug 61

Leukemia-associated Rho guanine nucleotide exchange factor (LARG) was originally identified as a fusion partner with mixed-lineage leukemia in a patient with acute myeloid leukemia. LARG possesses a tandem Dbl homology and pleckstrin homology domain structure and, consequently, may function as an activator of Rho GTPases. In this study, we demonstrate that LARG is a functional Dbl protein. Expression of LARG in cells caused activation of the serum response factor, a known downstream target of Rho-mediated signaling pathways. Transient overexpression of LARG did not activate the extracellular signal-regulated kinase or c-Jun NH(2)-terminal kinase mitogen-activated protein kinase cascade, suggesting LARG is not an activator of Ras, Rac, or Cdc42. We performed in vitro exchange assays where the isolated Dbl homology (DH) or DH/pleckstrin homology domains of LARG functioned as a strong activator of RhoA, but exhibited no activity toward Rac1 or Cdc42. We found that LARG could complex with RhoA, but not Rac or Cdc42, in vitro, and that expression of LARG caused an increase in the levels of the activated GTP-bound form of RhoA, but not Rac1 or Cdc42, in vivo. Thus, we conclude that LARG is a RhoA-specific guanine nucleotide exchange factor. Finally, like activated RhoA, we determined that LARG cooperated with activated Raf-1 to transform NIH3T3 cells. These data demonstrate that LARG is the first functional Dbl protein mutated in cancer and indicate LARG-mediated activation of RhoA may play a role in the development of human leukemias.
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PMID:Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. 1137 93

Interactions between the checkpoint abrogator UCN-01 and several pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway have been examined in a variety of human leukemia cell lines. Exposure of U937 monocytic leukemia cells to a marginally toxic concentration of UCN-01 (e.g., 150 nM) for 18 h resulted in phosphorylation/activation of p42/44 MAPK. Coadministration of the MEK inhibitor PD184352 (10 microM) blocked UCN-01-induced MAPK activation and was accompanied by marked mitochondrial damage (e.g., cytochrome c release and loss of DeltaPsi(m)), caspase activation, DNA fragmentation, and apoptosis. Similar interactions were noted in the case of other MEK inhibitors (e.g., PD98059; U0126) as well as in multiple other leukemia cell types (e.g., HL-60, Jurkat, CCRF-CEM, and Raji). Coadministration of PD184352 and UCN-01 resulted in reduced binding of the cdc25C phosphatase to 14-3-3 proteins, enhanced dephosphorylation/activation of p34(cdc2), and diminished phosphorylation of cyclic AMP-responsive element binding protein. The ability of UCN-01, when combined with PD184352, to antagonize cdc25C/14-3-3 protein binding, promote dephosphorylation of p34(cdc2), and potentiate apoptosis was mimicked by the ataxia telangectasia mutation inhibitor caffeine. In contrast, cotreatment of cells with UCN-01 and PD184352 did not substantially increase c-Jun-NH(2)-terminal kinase activation nor did it alter expression of Bcl-2, Bcl-x(L), Bax, or X-inhibitor of apoptosis. However, coexposure of U937 cells to UCN-01 and PD184352 induced a marked increase in p38 MAPK activation. Moreover, SB203580, which inhibits multiple kinases including p38 MAPK, partially antagonized cell death. Lastly, although UCN-01 +/- PD184352 did not induce p21(CIP1), stable expression of a p21(CIP1) antisense construct significantly increased susceptibility to this drug combination. Together, these findings indicate that exposure of leukemic cells to UCN-01 leads to activation of the MAPK cascade and that interruption of this process by MEK inhibition triggers perturbations in several signaling and cell cycle regulatory pathways that culminate in mitochondrial injury, caspase activation, and apoptosis. They also raise the possibility that disrupting multiple signaling pathways, e.g., by combining UCN-01 with MEK inhibitors, may represent a novel antileukemic strategy.
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PMID:Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. 1143 48

The proto-oncogene c-Jun has been implicated in the control of cell proliferation and differentiation and more recently in the regulation of apoptosis. We have previously reported the involvement of c-Jun in the erythroid differentiation block in murine erythroleukemia (MEL) cells. As reported here, we investigated the role of c-Jun in the regulation of terminal differentiation and apoptosis of MEL cells by studying different stable transfectant clones containing c-jun constructs in sense or antisense orientation. c-Jun did not prevent cell growth arrest in G0/G1 and p21 induction that are normally associated with terminal differentiation induced by DMSO treatment, suggesting that c-Jun may uncouple phenotypic differentiation and terminal cell division in the MEL cell system. Spontaneous apoptosis was accelerated in c-jun expressing MEL cells before and after DMSO treatment. Moreover, c-Jun sensitized apoptosis induced by various drugs. Drug-induced apoptosis was associated with c-Jun N-terminal kinase (JNK) activation and c-Jun N-terminal phosphorylation (JNP). In contrast, overexpression of c-jun delayed apoptosis in serum-starved cells, indicating that c-Jun may reduce or accelerate apoptosis in MEL cells depending on the nature of the apoptotic stimulus. These results suggest that the proto-oncogene c-Jun may modulate differentiation and apoptosis of leukemic cells.
Leukemia 2002 Feb
PMID:C-Jun modulates apoptosis but not terminal cell differentiation in murine erythroleukemia cells. 1184 Feb 90

We previously showed that cepharanthine (CEP), a biscoclaurine alkaloid, induces caspase-dependent and Fas-independent apoptosis in Jurkat and K562 human leukemia cells. In the present study, we investigated the effect of CEP on three groups of human mitogen-activated protein kinases (MAPKs) in relation to CEP-induced apoptosis. CEP, at the concentration required for and at the time of induction of apoptosis, activated MAPKs p38 in both Jurkat and K562 cells and activated extracellular signal-regulated kinases (ERKs) only in K562 cells. However, CEP treatment did not trigger c-Jun NH(2)-terminal kinases (JNKs) activation. CEP increased the expression and phosphorylation levels of c-Jun and ATF-2 transcription factors. zVAD-fmk, a general caspase inhibitor, did not inhibit CEP-triggered p38 activation in Jurkat and K562 cells or ERK activation in K562 cells. Unexpectedly, pretreatment with a specific p38 inhibitor, SB203580, promoted CEP-induced apoptosis and caspase activation in Jurkat and K562 cells, whereas pretreatment with an MEK-1 inhibitor PD98059 inhibited CEP-induced apoptosis and caspase activation in K562 cells. A selective tyrosine kinase inhibitor, herbimycin A, which completely inhibited CEP-triggered ERKs activation, clearly promoted CEP-induced c-Jun expression and phosphorylation. Our results suggest that each of the three groups of MAP family members is uniquely involved in the CEP-mediated signal cascades in two different leukemia cell lines for inducing/regulating caspase activation and DNA fragmentation.
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PMID:Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. 1189 91

The exposure of mammalian cells to UV irradiation induces the expression of immediate early genes such as c-jun and c-fos and activates the transcription factors AP-1 and NF-kappaB. JunD is one of the three members of the Jun family and shares some functional characteristics with c-Jun. In the present study, we found that the exposure of myeloblastic leukemia ML-1 cells to UV light (UVC) caused a significant increase in junD mRNA expression within 5 min that persisted for a period of 3 h. The activation of protein kinase C (PKC) with 12-O-tetradecaoylphorbol-13-acetate (TPA) also induced increases in junD expression similar to those of UV irradiation. In addition, UV irradiation- and TPA-induced increases in junD expression were completely abolished by GF-109203X, a PKC-specific inhibitor. UV irradiation activated intracellular signaling pathways including extracellular regulated kinase-2 (Erk-2), c-Jun N-terminal kinases-1 (JNK-1), and p38. However, TPA-induced activation of PKC affected only Erk-2 activity, and GF-109203X (a PKC inhibitor) markedly suppressed UV-induced Erk-2 activation. To further investigate the effect of UV-induced Erk-2 activation on the expression of junD mRNA, cDNA encoding mitogen-activated protein kinase kinase (MEK1) was overexpressed in ML-1 cells. The overexpression of MEK1 enhanced substantially junD expression in response to UV or TPA. In contrast, the suppression of Erk activation with PD98059, a specific inhibitor of MEK1, inhibited UV- and TPA-induced junD mRNA expression, UV-induced increases in caspase-3 activities, and cell death. In addition, the overexpression of junD enhanced the UV irradiation-induced increases in caspase-3 activity and cell death. We conclude that UV irradiation-induced increases in junD expression in ML-1 cells are mediated through activation of the PKC-coupled Erk-2 signaling pathway and play an important role in ML-1 cell apoptosis.
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PMID:Ultraviolet-induced junD activation and apoptosis in myeloblastic leukemia ML-1 cells. 1208 1

1: In the haematopoietic microenvironment, bone marrow stromal cells play an important role in regulating haematopoiesis by expressing various cytokines, including leukaemia inhibitory factor (LIF) and interleukin-6 (IL-6). However, the intracellular signal that regulates cytokine secretion in bone marrow stromal cells has not been determined. The aim of this study was to evaluate the role of mitogen-activated protein kinase (MAPK) family in serum-induced secretion of LIF and IL-6 by bone marrow stromal cells. 2: Transformed human bone marrow stromal cells (HS-5) were stimulated with foetal calf serum (FCS) to produce LIF and IL-6. FCS also induced activation of extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun NH(2)-terminal kinase (JNK). 3: Both PD98059 (MAPK/ERK kinase inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated FCS-induced LIF protein production and gene expression. SB203580 decreased IL-6 production and gene expression, but PD98059 had no effect on IL-6 production and gene expression. 4: Expression of a dominant-negative mutant form of JNK1 that blocked FCS-induced JNK activity had no effect on protein production and gene expression of these cytokines. 5: These findings demonstrate that both ERK and p38 MAPK are involved in FCS-induced LIF secretion, whereas only p38 MAPK is important for IL-6 secretion, and that FCS-induced activation of JNK has no effect on the production of LIF and IL-6. We conclude that, in spite of their similar biological effects, they are differentially regulated at the level of MAPK activity in bone marrow stromal cells.
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PMID:Role of mitogen-activated protein kinase family in serum-induced leukaemia inhibitory factor and interleukin-6 secretion by bone marrow stromal cells. 1214 97


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