Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of Exisulind on the viability and apoptosis of CD34(+) stem cells from patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)/MDS was investigated. In eight out of 10 patient samples Exisulind reduced the fraction of viable cells by inducing apoptosis. We found evidence that Exisulind-mediated apoptosis depends on c-Jun NH(2)-terminal kinase (JNK) activation. Addition of a specific JNK-inhibitor to Exisulind-treated advanced MDS and AML/MDS cells partly abrogated apoptosis. We propose that Exisulind is tested in clinical phase I/II trials for the treatment of advanced MDS and AML/MDS.
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PMID:Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS. 1697 22

Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1-knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.
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PMID:Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. 1704 2

hCDC4 (FBW7, FBXW7) is a new potential tumor suppressor gene which provides substrate specificity for SCF (Skp-Cullin-F-box) ubiquitin ligases and thereby regulates the degradation of potent oncogenes such as cyclin E, Myc, c-Jun and Notch. Mutations in the hCDC4 gene have been found in several solid tumors such as pancreas, colorectal or endometrial cancer. We carried out a mutation analysis of the hCDC4 gene in 35 samples of patients with Acute Myeloid Leukemia (AML) to elucidate a possible role of hCDC4 mutations in this disease. By direct DNA sequencing and digestion with Surveyor nuclease one heterozygous mutation in the 5' untranslated region of exon 1, transcript variant 3 was detected. Additionally, we could identify a new intronic SNP downstream of exon 10. The new variation was present in 20% of AML samples and was furthermore confirmed in a panel of 51 healthy individuals where it displayed a frequency of 14%. In conclusion we provide first data that in contrast to several solid tumors, mutations in the hCDC4 gene may not play a pivotal role in the pathogenesis of AML. Furthermore, we describe a new intronic polymorphism with high frequency in the intron sequence of the hCDC4 gene.
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PMID:Mutation analysis of hCDC4 in AML cells identifies a new intronic polymorphism. 1708 41

HoxA10 is a homeodomain transcription factor that is frequently overexpressed in human acute myeloid leukemia. In murine bone marrow transplantation studies, HoxA10 overexpression induces a myeloproliferative disorder with accumulation of mature phagocytes in the peripheral blood and tissues. Over time, differentiation block develops in these animals, resulting in acute myeloid leukemia. In immature myeloid cells, HoxA10 represses transcription of some genes that confer the mature phagocyte phenotype. Therefore, overexpressed HoxA10 blocks differentiation by repressing myeloid-specific gene transcription in differentiating myeloid cells. In contrast, target genes involved in myeloproliferation due to HoxA10 overexpression have not been identified. To identify such genes, we screened a CpG island microarray with HoxA10 co-immunoprecipitating chromatin. We identified the DUSP4 gene, which encodes mitogen-activated protein kinase phosphatase 2 (Mkp2), as a HoxA10 target gene. We analyzed the DUSP4 5'-flank and identified two proximal-promoter cis elements that are activated by HoxA10. We find that DUSP4 transcription and Mkp2 expression decrease during normal myelopoiesis. However, this down-regulation is impaired in myeloid cells overexpressing HoxA10. In hematopoietic cells, c-Jun N-terminal kinases (Jnk) are the preferred substrates for Mkp2. Therefore, Mkp2 inhibits apoptosis by dephosphorylating (inactivating) Jnk. Consistent with this, HoxA10 overexpression decreases apoptosis in differentiating myeloid cells. Therefore, our studies identify a mechanism by which overexpressed HoxA10 contributes to inappropriate cell survival during myelopoiesis.
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PMID:HoxA10 activates transcription of the gene encoding mitogen-activated protein kinase phosphatase 2 (Mkp2) in myeloid cells. 1743 Aug 93

The family of statins includes pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase that are potent regulators of cholesterol biosynthesis. In addition to their cholesterol-lowering effects, statins inhibit cell proliferation and promote apoptosis of malignant cells in vitro, but their potential therapeutic roles in the treatment of malignancies remain to be defined. We examined the effects of statins on the growth and differentiation of acute myeloid leukemia (AML) cells. Atorvastatin and fluvastatin were found to be potent inducers of cell differentiation and apoptosis of the NB4 acute promyelocytic leukemia (APL) cell line. Such effects correlated with activation of the small G-proteins Rac1/Cdc42 and downstream engagement of the c-Jun NH(2)-terminal kinase kinase pathway, whose function was found to be essential for the generation of proapoptotic responses. Importantly, different statins were found to enhance all-trans-retinoic acid (ATRA)-dependent differentiation of APL blasts and reverse resistance to the antileukemic effects of ATRA. In addition, fluvastatin exhibited growth-inhibitory properties on primary bone marrow-derived leukemic progenitors from patients with AML and enhanced the suppressive effects of ATRA on leukemic progenitor colony formation. Altogether, these studies establish that statins exhibit potent antileukemic properties in vitro and raise the possibility that combinations of statins with ATRA may be an effective approach to overcome the development of ATRA resistance by the leukemic cells.
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PMID:Suppressive effects of statins on acute promyelocytic leukemia cells. 1748 69

Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.
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PMID:Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. 1751 97

Mef2c is a MADS (MCM1-agamous-deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2c(Delta/-) mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBPalpha, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity--and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.
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PMID:The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate. 1832 19

IL-18 production may enhance immune system defense against KG-1 cells ; NB4 cells, which are associated with good prognosis, do not produce IL-18. In this study, we treated KG-1 cells with IL-18 and used microarray technology to assess subsequent effects on gene expression. In UniGene-array of 7488 human genes, expression of 57 genes, including stress related genes, increased at least 2-fold, whereas expression of 48 genes decreased at least 2-fold. Following exogenous exposure of KG-1 cells to IL-18, expression of CRYGC, NF(kappa)BIA and NACA gene were monitored. The latter is a transcriptional coactivator potentiating c-Jun-mediated transcription. NF(kappa)BIA is an inhibitor of NF(kappa)B, and affects growth regulation, apoptosis and hypoxic stress. Studies, such as this one, are beginning to clarify the differences between cells associated with good and bad cancer prognoses, which may ultimately assist in medical treatment for acute myeloid leukemia.
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PMID:IL-18 gene expression pattern in exogenously treated AML cells. 1859 30

To potentiate the response of acute myelogenous leukemia (AML) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity, we have examined the efficacy of a combination with perifosine, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor. The rationale for using such a combination is that perifosine was recently described to increase TRAIL-R2 receptor expression and decrease the cellular FLICE-inhibitory protein (cFLIP) in human lung cancer cell lines. Perifosine and TRAIL both induced cell death by apoptosis in the THP-1 AML cell line, which is characterized by constitutive PI3K/Akt activation, but lacks functional p53. Perifosine, at concentrations below IC(50), dephosphorylated Akt and increased TRAIL-R2 levels, as shown by Western blot, reverse transcription-PCR, and flow cytometric analysis. Perifosine also decreased the long isoform of cFLIP (cFLIP-L) and the X-linked inhibitor of apoptosis protein (XIAP) expression. Perifosine and TRAIL synergized to activate caspase-8 and induce apoptosis, which was blocked by a caspase-8-selective inhibitor. Up-regulation of TRAIL-R2 expression was dependent on a protein kinase Calpha/c-Jun-NH(2)-kinase 2/c-Jun signaling pathway activated by perifosine through reactive oxygen species production. Perifosine also synergized with TRAIL in primary AML cells displaying constitutive activation of the Akt pathway by inducing apoptosis, Akt dephosphorylation, TRAIL-R2 up-regulation, cFLIP-L and XIAP down-regulation, and c-Jun phosphorylation. The combined treatment negatively affected the clonogenic activity of CD34(+) cells from patients with AML. In contrast, CD34(+) cells from healthy donors were resistant to perifosine and TRAIL treatment. Our findings suggest that the combination of perifosine and TRAIL might offer a novel therapeutic strategy for AML.
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PMID:Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. 1901 Sep 14

The block of hematopoietic differentiation program in acute myeloid leukemia cells can be overcome by differentiating agent like retinoic acid, but it has several side effects. A study of other differentiation signaling pathways is therefore useful to predict potential targets of anti-leukemic therapy. We demonstrated previously that the co-treatment of HL-60 cells with Tumor necrosis factor-alpha (TNF-alpha) (1 ng/mL) and inhibitor of 5-lipoxygenase MK886 (5 microm) potentiated both monocytic differentiation and apoptosis. In this study, we detected enhanced activation of three main types of mitogen-activated protein kinases (MAPKs) (p38, c-Jun amino-terminal kinase [JNK], extracellular signal-regulated kinase [ERK]), so we assessed their role in differentiation using appropriate pharmacologic inhibitors. The inhibition of pro-apoptotic MAPKs (p38 and JNK) suppressed the effect of MK886 + TNF-alpha co-treatment. On the other hand, down-regulation of pro-survival ERK pathway led to increased differentiation. Those effects were accompanied by increased activation of caspases in cells treated by MK886 + TNF-alpha. Pan-caspase inhibitor ZVAD-fmk significantly decreased both number of apoptotic and differentiated cells. The same effect was observed after inhibition of caspase 9, but not caspase 3 and 8. To conclude, we evidenced that the activation of apoptotic processes and pathways supporting apoptosis (p38 and JNK MAPKs) is required for the monocytic differentiation of HL-60 cells.
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PMID:Monocytic differentiation of leukemic HL-60 cells induced by co-treatment with TNF-alpha and MK886 requires activation of pro-apoptotic machinery. 1922 Apr 23


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