Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression status of mitochondrial uncoupling protein 2 (UCP2) was investigated in undifferentiated mouse myeloid leukemia (M1) and its differentiated macrophage-like cells (Mm1). Mm1 cells have a high ability of phagocytosis along with significantly high levels of reactive oxygen species (ROS) production, UCP2 protein and manganese superoxide dismutase (Mn-SOD), in contrast to undifferentiated leukemia cells (M1). Mm1 cells expressed 10-fold more UCP2 protein compared with undifferentiated M1 cells, although the UCP2 mRNA levels in both cell types were similar. The higher expression of UCP2 in the Mm1 cells suggests a regulatory role of UCP2 in the ROS production. Furthermore, the transfection of UCP2-GFP-expression vector in Mm1 cells dissipated the mitochondrial membrane potential and reduced ROS production, which was shown by their direct visualization using MitoTracker Red CM-H2Xros. The macrophage gp91phox protein, a membrane catalytic component of the NADPH oxidase complex, was at a similar level in both of UCP2-GFP expressed and non-expressed Mm1 cells. These results suggest that the UCP2 protein of the undifferentiated cell is regulated at a quite low level and the higher UCP2 protein of the differentiated macrophages involves with the regulation of ROS production.
J Mol Histol 2005 Feb
PMID:Characterization of the differential expression of uncoupling protein 2 and ROS production in differentiated mouse macrophage-cells (Mm1) and the progenitor cells (M1). 1570 97

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
Mol Cancer Ther 2005 Mar
PMID:Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. 1576 47

The interleukin-6 (IL-6) stimulates growth in cells such as multiple myeloma and B-cell plasmacytomas/hybridomas, while it inhibits growth in several myeloid leukemia cells. The IL-6 receptor has subunit called gp130. It was reported that Ser-782 of gp130 is phosphorylated by unidentified kinase(s) in cell extracts, and level of gp130 (S782A) transiently expressed on the cell surface of COS-7 is 6-times higher than that of the wild type. These results motivated us to analyze whether the phosphorylation of gp130 at Ser-782 is involved in its degradation or not. In this study, we demonstrated here that treatment of HepG2 cells with okadaic acid (OA), a potent inhibitor for PP2A, promotes phosphorylation of gp 130 at Ser-782 and degradation of gp 130. MG115, a proteasome inhibitor, suppressed this degradation. These effects of OA could not be replaced with tautomycetin (TC), an inhibitor for PP1. Purified PP2A dephosphorylated phospho-Ser-782 of gp130 in vitro. IL-6-induced activation of Stat3 was suppressed by preincubation of the cells with OA, suggesting that the IL-6 signaling pathway was blocked by OA through degradation of gp 130. Taken together, present results strongly suggest that degradation of gp 130 is regulated through a phosphorylation-dephosphorylation mechanism in which PP2A is crucially involved and that gp 130 is a potential therapeutic target in cancers.
Mol Cell Biochem 2005 Jan
PMID:Protein phosphatase type 2A, PP2A, is involved in degradation of gp130. 1578 31

Fusion of the MN1 gene to TEL (ETV6) results in myeloid leukemia. The fusion protein combines the transcription activating domain of MN1 and the DNA binding domain of TEL and is thought to act as a deranged transcription factor. In addition, disruption of the large first exon of the MN1 gene is thought to inactivate MN1 function in a meningioma. To further investigate the role of MN1 in cancer, we generated Mn1 knockout mice. Mn1(+/-) animals were followed for 30 months, but they had no higher incidence of tumor formation than wild-type littermates. Mn1 null mice, however, were found to die at birth or shortly thereafter as the result of a cleft palate. Investigation of newborn or embryonic day 15.5 (E15.5) to E17.5 null mice revealed that the development of several bones in the skull was abnormal. The affected bones are almost exclusively formed by intramembranous ossification. They are either completely agenic at birth (alisphenoid and squamosal bones and vomer), hypoplastic, deformed (basisphenoid, pterygoid, and presphenoid), or substantially thinner (frontal, parietal, and interparietal bones). In heterozygous mice hypoplastic membranous bones and incomplete penetrance of the cleft palate were observed. We conclude that Mn1 is an important factor in development of membranous bones.
Mol Cell Biol 2005 May
PMID:Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton. 1587 Feb 92

Intracellular inclusions of abnormally long polyglutamine tracts and neurotoxicity are the hallmarks of several hereditary neurodegenerative disorders, including Huntington's disease (HD). In Drosophila melanogaster, dMLF, an ortholog of human myeloid leukemia factors, hMLF1 and hMLF2, suppressed polyglutamine toxicity and colocalized with the inclusions. In transfected primary rat neuronal cultures, dMLF and its orthologs reduced the morphological phenotypes and inclusions. Furthermore, dMLF reduced the recruitment of CBP and Hsp70 into the inclusions, both of which are among many essential proteins apparently trapped in the inclusions. These data suggest that a possible mechanism of suppression by dMLF is via the sequestration of polyglutamine oligomers or inclusions.
Mol Cell Neurosci 2005 Aug
PMID:Evidence for sequestration of polyglutamine inclusions by Drosophila myeloid leukemia factor. 1593 12

The oncogenic TLS-ERG fusion protein is found in human myeloid leukemia and Ewing's sarcoma as a result of specific chromosomal translocation. To unveil the potential mechanism(s) underlying cellular transformation, we have investigated the effects of TLS-ERG on both gene transcription and RNA splicing. Here we show that the TLS protein forms complexes with RNA polymerase II (Pol II) and the serine-arginine family of splicing factors in vivo. Deletion analysis of TLS-ERG in both mouse L-G myeloid progenitor cells and NIH 3T3 fibroblasts revealed that the RNA Pol II-interacting domain of TLS-ERG resides within the first 173 amino acids. While TLS-ERG repressed expression of the luciferase reporter gene driven by glycoprotein IX promoter in L-G cells but not in NIH 3T3 cells, the fusion protein was able to affect splicing of the E1A reporter in NIH 3T3 cells but not in L-G cells. To identify potential target genes of TLS-ERG, the fusion protein and its mutants were stably expressed in both L-G and NIH 3T3 cells through retroviral transduction. Microarray analysis of RNA samples from these cells showed that TLS-ERG activates two different sets of genes sharing little similarity in the two cell lines. Taken together, these results suggest that the oncogenic TLS-ERG fusion protein transforms hematopoietic cells and fibroblasts via different pathways.
Mol Cell Biol 2005 Jul
PMID:The oncogenic TLS-ERG fusion protein exerts different effects in hematopoietic cells and fibroblasts. 1598 32

The prognostic significance of selected markers of leukemic cells is well known. CD7 and CD56 expression at diagnosis has been associated with low remission rates and biological aggressiveness in a significant proportion of acute leukemias. Among 46 patients with acute myeloid leukemia, we found CD7 expression in 15 cases (32.6%) and CD56 positivity in 10 patients (21.7%). Six of these myeloid leukemia cases (13%) showed expression of both CD7 and CD56. Four of 46 (8.7%) patients expressed CD79a. Among the 10 that were acute myeloblastic leukemia, 8 expressed CD7, 4 expressed CD56, and 4 were positive for CD79a. Thus, these markers were expressed early in hemopoietic ontogeny in the lesser-differentiated acute myeloid leukemia subtypes, including FAB M0, M1, and M2. Whereas CD7 and CD56 were each positive in 4 cases of acute myelomonocytic leukemia (FAB M4 subtype), there was no CD79a expression in the M4 cases. CD7 is expressed by mature T cells, NK cells, and an immature myeloid cell subset. NK cells and a T cell subset express CD56. By contrast, CD79a is a B cell marker that is assigned a high score of 2.0 in the differentiation of acute leukemias of ambiguous lineage in the WHO classification. The aberrant expression of CD7, CD56, and CD79a, representing the capacity of these leukemias for trilineal expression of leukocyte differentiation antigens, portends a poor prognosis.
Exp Mol Pathol 2005 Aug
PMID:Aberrant expression of CD7, CD56, and CD79a antigens in acute myeloid leukemias. 1600 10

The MLL gene, located within band 11q23, has been shown to be involved in translocations with a large variety of reciprocal sites in both lymphoid and myeloid leukemia and has also been shown to undergo submicroscopic self-fusion/partial duplication. We report 29 patients with cytogenetic evidence of 11q23 alteration, all of which demonstrate molecular cytogenetic evidence of amplification of the MLL gene by fluorescence in situ hybridization (FISH). In all MLL cases, the patients were clinically classified as having transforming myelodysplasia (RAEB/RAEBT) or AML. An additional patient with AML was found by 24-color and gene-specific FISH to have AML1 oncogene amplification. Four patients had been previously diagnosed with cancer and had received topoisomerase II targeted drug therapy which is known to be associated with fusion transcripts involving the MLL and AML1 genes. MLL amplification appeared in various forms: an atypical banded region that bridges from 11q23 into a dicentric chromosome, expanded regions emanating from band 11q23, chromosome 11 paint-positive rings with "spoke-like" MLL amplification, and expansion at sites other than chromosome 11 (including extra markers) in the absence of one of the 11 homologues. The fluorescence pattern in most cases suggests palindromic duplication with neighboring sequences in the long arm of chromosome 11. As opposed to MYCN amplification in hsrs (homogeneously staining regions) and double minutes in neuroblastoma, amplification of MLL in most cases occurred at the site of the gene. All of our patients rapidly developed refractory AML. The frequency and clinical correlations of MLL gene amplification in leukemia will need careful follow-up, since the frequently cryptic amplification described in these cases may not generally provoke confirmatory FISH studies. The reported MLL cases represented about 1% of the total abnormal MDS/AML cases over 8 years. A common cytogenetic profile of 5 q-, -17/17 p-, -18/18 q-, and a missing or abnormal chromosome 11, may help direct appropriate follow-up studies. The MLL and the AML1 oncogenes appear to be the only oncogenes amplified at the natural site of the gene. Both genes also show a high degree of diversity of pathogenic mechanisms of leukemia evolution, including numerous reciprocal fusion genes in transformation to either AML or ALL and gain of function amplification.
Exp Mol Pathol 2005 Oct
PMID:Oncogene amplification in transforming myelodysplasia. 1602 82

The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPbeta. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2) D(3)). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1alpha,25(OH)(2) D(3). Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPbeta, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPbeta paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPbeta bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
J Steroid Biochem Mol Biol 2005 Oct
PMID:The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway. 1604 62

Depleted uranium (DU) is a dense heavy metal used in military applications. During military conflicts, US military personnel have been wounded by DU shrapnel. The health effects of embedded DU are unknown. Published data from our laboratory demonstrated that DU exposure in vitro can transform immortalized human osteoblast cells (HOS) to the tumorigenic phenotype. Results from our laboratory have also shown that DU is genotoxic and mutagenic in cultured human cells. Internalized DU could be a carcinogenic risk and concurrent alpha particle and heavy metal toxic effects complicate this potential risk. Anecdotal reports have suggested that DU can cause leukemia. To better assess this risk, we have developed an in vivo leukemogenesis model. This model involves using murine hematopoietic cells (FDC-P1) that are dependent on stimulation by granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3) and injected into mice to produce myeloid leukemia. Although immortalized, these cells are not tumorigenic on subcutaneous inoculation in mice. Intravenous injection of FDC-P1 cells into DU-implanted DBA/2 mice was followed by the development of leukemias in 76% of all mice implanted with DU pellets. In contrast, only 12% of control mice developed leukemia. Karyotypic analysis confirmed that the leukemias originated from FDC-P1 cells. The growth properties of leukemic cells from bone marrow, spleen, and lymph node were assessed and indicate that the FDC-P1 cells had become transformed in vivo. The kidney, spleen, bone marrow, muscle, and urine showed significant elevations in tissue uranium levels prior to induction of leukemia. These results demonstrated that a DU altered in vivo environment may be involved in the pathogenesis of DU induced leukemia in an animal model.
Mol Cell Biochem 2005 Nov
PMID:Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium. 1628 18


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