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)

The cytoplasmic domains of the transmembrane (TM) envelope proteins (TM-CDs) of most retroviruses have a Tyr-based motif, YXXO, in their membrane-proximal regions. This signal is involved in the trafficking and endocytosis of membrane receptors via clathrin-associated AP-1 and AP-2 adaptor complexes. We have used CD8-TM-CD chimeras to investigate the role of the Tyr-based motif of human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), and human T-leukemia virus type 1 (HTLV-1) TM-CDs in the cell surface expression of the envelope glycoprotein. Flow cytometry and confocal microscopy studies showed that this motif is a major determinant of the cell surface expression of the CD8-HTLV chimera. The YXXO motif also plays a key role in subcellular distribution of the envelope of lentiviruses HIV-1 and SIV. However, these viruses, which encode TM proteins with a long cytoplasmic domain, have additional determinants distal to the YXXO motif that participate in regulating cell surface expression. We have also used the yeast two-hybrid system and in vitro binding assays to demonstrate that all three retroviral YXXO motifs interact with the micro1 and micro2 subunits of AP complexes and that the C-terminal regions of HIV-1 and SIV TM proteins interact with the beta2 adaptin subunit. The TM-CDs of HTLV-1, HIV-1, and SIV also interact with the whole AP complexes. These results clearly demonstrate that the cell surface expression of retroviral envelope glycoproteins is governed by interactions with adaptor complexes. The YXXO-based signal is the major determinant of this interaction for the HTLV-1 TM, which contains a short cytoplasmic domain, whereas the lentiviruses HIV-1 and SIV have additional determinants distal to this signal that are also involved.
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PMID:Interactions of the cytoplasmic domains of human and simian retroviral transmembrane proteins with components of the clathrin adaptor complexes modulate intracellular and cell surface expression of envelope glycoproteins. 988 40

Two interrelated cellular processes are invoked simultaneously upon induction of differentiation, the regulated progression of cells through successive stages of cell differentiation and growth inhibition which ultimately leads to growth arrest. In tissues with rapid cell turnover terminally differentiated cells undergo programmed cell death. Terminal differentiation, thus, represents one form of negative growth control. It was surmised that the molecular engine which drives the differentiation process forward requires induction of positive regulators of terminal cell differentiation, to be found among differentiation primary response genes, as well as suppression of negative regulators, which correspond to genes which control cellular growth. This line of thought has prompted the isolation of myeloid differentiation primary response (MyD) genes activated in the absence of de novo protein synthesis, upon IL-6 induced terminal differentiation of murine M1 myeloblastic leukemia cells, where the cells growth arrest and ultimately undergo programmed cell death. As delineated in this review many of the genes identified as MyD genes, including both known genes [IRF-1, (AP-1)Fos/Jun.EGR-1] and novel ones (MyD88, MyD116, MyD118), turned out to play a role in negative growth control, including growth suppression and apoptosis, in many cell types, of both hematopoietic and non hematopoietic origins.
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PMID:MyD genes in negative growth control. 991 94

A number of studies have reported that human leukemia cells respond to exposure to power-line frequency electromagnetic fields (EMFs), providing evidence for an EMF-induced signaling pathway involving activation of protein tyrosine kinases (PTKs), phospholipase-Cy and protein kinase C (PKC). Because activation of PKC is also important in the signaling pathways that regulate the transcription factors NF-kappaB and AP-1, we evaluated the effect of exposure to a 60 Hz EMF on NF-kappaB or AP-1-dependent reporter gene expression in cells of the human promonocytic U937 leukemia cell line. Reporter genes were electroporated into U937 cells and activation of the NF-kappaB or AP-1 signaling pathway was evaluated by measuring chloramphenicol acetyltransferase (CAT) protein by CAT ELISA. In contrast to the effects of well-understood chemical or biological agents, the exposure to magnetic-field intensities of 0.08, 0.1, 1.0 or 1.3 mT had no effect on the NF-kappaB or AP-1 signaling pathways.
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PMID:NF-kappaB or AP-1-dependent reporter gene expression is not altered in human U937 cells exposed to power-line frequency magnetic fields. 1007 69

Because of the increasing use of IFN-alpha in both induction and maintenance therapy for multiple myeloma (MM), its effect on growth and apoptosis of myeloma cells is important to consider. To investigate the role of IFN-alpha on the growth of myeloma cells, we have studied its effects on the response of interleukin 6 (IL-6)-dependent myeloma cell line (ANBL6) and IL-6-independent myeloma cell line (C2E3) in the presence of IL-6 and dexamethasone (Dex). We found that although IFN-alpha is a potent inhibitor of proliferation, it has only a minimal effect on induction of apoptosis. Moreover, we found IFN-alpha as well as IL-6 can significantly suppress dexamethasone-induced apoptosis. The suppression of apoptosis is concurrent with the induction of both AP-1 and STAT binding activity. We also found that IL-6 but not IFN-alpha up-regulates Bcl-X(L) expression. However, IL-6-mediated Bcl-X(L) expression is suppressed in the presence of Dex. Therefore, the expression of Bcl-X(L) does not account for the protection of Dex-induced apoptosis by IFN-alpha and IL-6. Taken together, our results suggest that IFN-alpha may counteract the beneficial effects of corticosteroids or perhaps other apoptosis inducing agents in the treatment of myeloma.
Leukemia 1999 Mar
PMID:Interferon-alpha protects myeloma cell lines from dexamethasone-induced apoptosis. 1008 39

Leukemia and lymphoma induced by feline leukemia viruses (FeLVs) are the commonest forms of illness in domestic cats. These viruses do not contain oncogenes, and the source of their pathogenic activity is not clearly understood. Mechanisms involving proto-oncogene activation subsequent to proviral integration and/or development of recombinant viruses with enhanced replication properties are thought to play an important role in their disease pathogenesis. In addition, the long terminal repeat (LTR) regions of these viruses have been shown to be important determinants for pathogenicity and tissue specificity, by virtue of their ability to interact with various transcription factors. Previously, we have shown that, in the case of Moloney murine leukemia virus, the U3 region of the LTR independently induces transcriptional activation of specific cellular genes through an LTR-generated RNA transcript (S. Y. Choi and D. V. Faller, J. Biol. Chem. 269:19691-19694, 1994; S.-Y. Choi and D. V. Faller, J. Virol. 69:7054-7060, 1995). In this report, we show that the U3 region of exogenous FeLV LTRs can induce transcription from collagenase IV (matrix metalloproteinase 9) and monocyte chemotactic protein 1 (MCP-1) promoters up to 12-fold. We also show that AP-1 DNA-binding activity and transcriptional activity are strongly induced in cells expressing FeLV LTRs and that LTR-specific RNA transcripts are generated in those cells. Activation of mitogen-activated protein kinase kinases 1 and 2 (MEK1 and -2) by the LTR is an intermediate step in the FeLV LTR-mediated induction of AP-1 activity. These findings thus suggest that the LTRs of FeLVs can independently activate transcription of specific cellular genes. This LTR-mediated cellular gene transactivation may play an important role in tumorigenesis or preleukemic states and may be a generalizable activity of leukemia-inducing retroviruses.
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PMID:Feline leukemia virus long terminal repeat activates collagenase IV gene expression through AP-1. 1023 55

Glucocorticoids (GC) are known to induce programmed cell death (apoptosis) in certain hematologic malignancies, but the molecular basis of this clinically significant phenomenon is poorly understood. GC act via binding to their specific receptor, a ligand-activated transcription factor, and might induce apoptosis by transcriptional activation of "death" or repression of "survival" genes. GC regulate gene expression directly, i.e. via GC responsive elements, or indirectly by modulating the activity of other transcription factors such as AP-1, NF-KB, Oct, Ets, and CREB. To analyze possible alterations in the activity of these transcription factors during GC-induced apoptosis, we performed electrophoretic mobility shift assays using the human acute T-cell leukemia line CCRF-CEM C7H2 as a model system. Although AP-1 was highly inducible by phorbol ester treatment, it was almost undetectable in logarithmically growing cells and apparently unregulated during GC-induced apoptosis. Thus, alterations in AP-1 activity do not appear to be involved in GC-induced apoptosis. Oct, Ets, and CREB DNA binding activity were detectable prior to and during GC treatment, and appeared to have been down-regulated after 48 hours. At this time, however, cells had already undergone considerable apoptosis, and this downregulation might reflect cell death-associated protein degradation. In contrast, NF-KB DNA binding activity was reduced 12 to 24 hours after GC exposure but reached levels equal to or higher than pre-treatment levels after 48 hours. Thus, while AP-1, Oct, Ets, and CREB may not be involved in GC-induced apoptosis, the maintenance of NF-KB levels suggests that it may participate in this form of cell death.
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PMID:Sequence-specific transcription factors during glucocorticoid-induced apoptosis in acute lymphoblastic leukemia cells. 1040 97

The effect of aflatoxin B1 (AFB1) on the interleukin-2 (IL-2) gene expression was investigated in thymocytes of B6C3F1 mice, Jurkat E6-1 human T-cell leukemia, and EL4.IL-2 murine thymoma. AFB1 inhibited the phorbol-12myristate-13-acetate/i6nomycin (PMA/Io)-induced IL-2 mRNA expression in the murine thymocytes and Jurkat E6-1 cells as determined by qualitative RT-PCR, while no effect was observed in the EL4.IL-2 cells. Electrophoretic mobility shift assay indicated that AFB1 treatment showed an inhibition of the NF-AT and AP-1 DNA binding in PMA/Io-stimulated thymocytes and Jurkat E6-1 cells. No effect was observed on the Oct and NF-kappaB DNA binding. Employing a reporter gene expression system with p(NF-AT)3-CAT and p(AP-1)3-CAT, treatment with AFB1 to the transfected Jurkat E6-1 cells also showed an inhibition of the PMA/Io-induced NF-AT/CAT and AP-1/CAT activities. These results suggest that suppression of the IL-2 gene expression by AFB1 is mediated through the down-regulation of the NF-AT and AP-1 activation.
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PMID:Suppression of the interleukin-2 gene expression by aflatoxin B1 is mediated through the down-regulation of the NF-AT and AP-1 transcription factors. 1047 4

Glucocorticoids have been used in the treatment of acute lymphoblastic leukaemia (ALL) for many years, initially as the only agent and then as part of multiagent chemotherapy. In ALL 20% of patients are resistant to glucocorticoids at presentation but this rises to greater than 70% on relapse. It has recently been reported that the glucocorticoid receptor inhibits activity of the AP-1 transcription factor by the ligand-dependant binding of glucocorticoid receptor (GR) to the fos and jun components of AP-1. Since AP-1 is necessary for cell proliferation, the upregulation or over-expression of AP-1 may be a mechanism of resistance to glucocorticoids. The aim of the study was to investigate whether AP-1 levels correlate with in vitro glucocorticoid resistance. In vitro sensitivity to glucocorticoids was measured using the MTT assay. AP-1 levels were quantified using gel shift analysis: a consensus sequence for the AP-1 binding site was synthesised, labelled with 32P and incubated with nuclear extracts of leukaemic blasts from 14 ALL and 26 CLL patients. Leukaemic blasts were treated with prednisolone or with vehicle alone before preparation of nuclear extracts. The gels were dried and bands quantified using a phosphorimager, using an appropriate internal standard and correcting for protein loading and cytoplasmic contamination of nuclear extracts. The patient samples fell into two distinct groups with respect to their sensitivity to glucocorticoids: AP-1 levels were significantly higher (p < 0.02) in sensitive blasts than resistant ones. There was no significant change in AP-1 levels after treating blasts for 4 hours with 0.2 mM prednisolone. No change was seen in CLL samples. These data show that glucocorticoid resistance is not associated with increased AP-1. Conversely, glucocorticoid resistance in these samples was apparently associated with decreased AP-1 levels in ALL samples. Whether this has any causal relationship to glucocorticoid resistance is unknown. Clearly, further studies on the role of AP-1 and related transcription factors is essential for understanding the control of proliferation and apoptosis in ALL.
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PMID:Glucocorticoid resistance and the AP-1 transcription factor in leukaemia. 1050 Aug 41

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

Tumour necrosis factor alpha (TNF-alpha) inflammatory activity is mediated, at least in part, by prostaglandin E(2)(PGE(2)). In osteoarthritis (OA), other cytokines are believed to play a role by interacting with TNF-alpha. Using OA synovial fibroblasts, we investigated the effects of interleukin 8 (IL-8), leukaemia inhibitory factor (LIF) and IL-11 on the level of TNF-alpha-induced PGE(2), and their impact on the TNF-alpha-induced cellular signalling cascades including the TNF-receptor (TNF-R), soluble TNF-R (TNF-sR), cytoplasmic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2), and the transcription factors NF-kappaB, C/EBP, CREB and AP-1.IL-8 increased in a synergistic manner (282% at 5 ng/ml) and LIF in an additive fashion (69% at 50 ng/ml) the TNF-alpha-induced PGE(2)release, while IL-11 reduced it (52% at 5 ng/ml). IL-8 (5 ng/ml) and LIF (50 ng/ml) alone upregulated (30%) the TNF-R binding level, but significantly downregulated the TNF-alpha-induced levels (P<0.007 and P<0.004, respectively) and the TNF-sR55 level. In contrast, IL-11 reduced the basal level by 18% (P<0.005) and the TNF-alpha-induced level of TNF-R by 51% (P<0.01) as well as decreasing both TNF-sR55 and TNF-sR75. The COX-2 synthesis level was increased by IL-8 and LIF under TNF-alpha treatment but downregulated by IL-11. IL-8 and LIF either alone or under TNF-alpha treatment increased the cPLA2 synthesis, while IL-11 decreased the level under both conditions. Interestingly, IL-8 induced in a synergistic manner and LIF in an additive fashion, the level of cPLA2 activity. IL-8 and LIF had no effect on the TNF-alpha-induced NF-kappaB accumulation, while IL-11 significantly decreased it (P<0. 02). All three cytokines inhibited TNF-alpha-induced C/EBP, but no true effect was noted for AP-1 and CREB in the presence of TNF-alpha. These results indicate that IL-8 synergizes and LIF potentiates the TNF-alpha PGE(2)effect which appears to be mediated mostly by increasing cPLA2 activity level. On the other hand, IL-11 alone had no effect on the PGE(2)release, but in conjunction with TNF-alpha, this cytokine showed anti-inflammatory properties. This study provides a rational foundation to develop therapeutic strategies for the treatment of OA by shedding light on the mechanisms of action of three prominent cytokines at work in articular joint tissues.
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PMID:Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE(2)release and on signalling pathways in human OA synovial fibroblasts. 1062 27


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