Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P67775 (alpha isoform)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A specific 'nested' reverse transcriptase/polymerase chain reaction (RT/PCR) procedure was used to characterize the expression patterns of PML-RAR-alpha chimeric mRNAs in 32 patients with acute promyelocytic leukemia (APL). The sensitivity of the technique was such that the fusion gene transcript could be detected from as little as 2.5 pg of total leukemic cell RNA against a background of 1 microgram of cellular RNA lacking the PML-RAR-alpha fusion gene transcript(s). In 19 cases the PML-RAR-alpha isoform referred to here as long was identified. A short isoform, which in comparison with the long form lacks three PML exons, was detected in 11 other cases. A third PML-RAR-alpha mRNA isoform, in which the most 3' PML exon present in the long-type isoform was truncated in its sequences lying immediately upstream of RAR-alpha B region, was found and characterized in a single patient. In one APL patient with a variant translocation t(11;17), the PCR product corresponding to PML-RAR-alpha chimeric mRNAs could not be amplified despite the presence of RAR-alpha gene rearrangement. Genomic and PCR analysis showed that the different PML-RAR-alpha isoforms found in APL patients arise as a result of distinct translocation breakpoints. In each case the exons encoding the B-F regions of RAR-alpha are expressed and are spliced downstream from variable PML gene exons. The 'nested' RT/PCR analysis of the PML-RAR-alpha fusion gene proved to be a rapid and sensitive tool for the diagnosis of the APL and for monitoring the residual APL chimeric mRNA expression during complete remission.
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PMID:Occurrence of distinct PML-RAR-alpha fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse transcriptase/polymerase chain reaction. 137 19

Certain protein kinase C (PKC) isotypes are localized to the nucleus during cellular proliferation in murine erythroid cells, as well as in human promyelocytic leukemia and erythroleukemia cells. Because the structure of these PKC isotypes contains a conserved cysteine-rich region that contains the zinc finger DNA binding motif, we tested the hypothesis that selected PKC isotypes found in Friend erythroleukemia cells can bind to DNA. Cell lysates from murine Friend erythroleukemia cells, which express alpha, beta I, and beta II PKC, expressed greater amounts of the beta isoforms than the alpha isoform of PKC in their nuclei, and PKC beta I was found in the chromatin of these cells. Lysates of these cells were tested for their ability to bind to a DNA-cellulose column. Bound proteins were eluted with a step gradient of increasing KCl concentrations, and eluant fractions were then subjected to immunoblot analysis using isotype-specific antibodies to the alpha and beta I isotypes of PKC. DNA binding was detected for the PKC beta I isotype, which is present in the nucleus, but not for the more abundant PKC alpha isotype, which resides primarily in the cytoplasm. These results demonstrate that PKC can associate with DNA, and that this association is isotype specific in Friend erythroleukemia cells.
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PMID:Protein kinase C beta from Friend erythroleukemia cells is associated with chromatin and DNA. 856 55

Topoisomerase II is a target for a number of chemotherapeutic agents used in the treatment of cancer. Its essential physiological role in modifying the topology of DNA involves the generation of transient double-strand breaks. Anti-cancer drugs, such as mitoxantrone, that target this enzyme interrupt its catalytic cycle and give rise to persistent double strand breaks, which may be lethal to a cell. We investigated the role of such lesions in signaling the activation of the transcription factor nuclear factor kappaB (NFkappaB) by this drug. Mitoxantrone activated NFkappaB and stimulated IkappaBalpha degradation in the promyelocytic leukemia cell line HL60 but not in the variant cells, HL60/MX2 cells, which lack the beta isoform of topoisomerase II and express a truncated alpha isoform that results in an altered subcellular distribution. Treatment of sensitive HL60 cells with mitoxantrone led to a depletion of both isoforms, suggesting the stabilization of transient DNA-topoisomerase II complexes. This depletion was absent in the variant cells, HL60/MX2. Activation of caspase 3 by mitoxantrone was also impaired in the HL60/MX2 cells. NFkappaB activation in response to tumor necrosis factor and bleomycin, the latter causing topoisomerase II-independent DNA damage, was intact in both cell lines. An inhibitor rather than a poison of topoisomerase II, Imperial Cancer Research Fund 187 (ICRF 187) the mechanism of which does not involve the generation of double strand breaks, did not activate NFkappaB, nor did it induce apoptosis in parental HL60 cells. However, ICRF 187 protected against IkappaB degradation in parental HL60 cells in response to mitoxantrone. This protection was also shown with another topoisomerase II inhibitor, merbarone, which is structurally and functionally distinct from ICRF 187. Their effects were specific, as neither protected against tumor necrosis factor-stimulated IkappaB degradation. The poisoning of topoiso- merase II with resultant DNA damage is therefore a critical signal for NFkappaB activation.
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PMID:Topoisomerase II is required for mitoxantrone to signal nuclear factor kappa B activation in HL60 cells. 1094 Mar 16

Previous results have shown that the human promyelocytic leukemia HL-60 cell line responds to either proliferating or differentiating stimuli. When these cells are induced to proliferate, protein kinase C (PKC)-beta II migrates toward the nucleus, whereas when they are exposed to differentiating agents, there is a nuclear translocation of the alpha isoform of PKC. As a step toward the elucidation of the early intranuclear events that regulate the proliferation or the differentiation process, we show that in the HL-60 cells, a proliferating stimulus (i.e., insulin-like growth factor-I [IGF-I]) increased nuclear diacylglycerol (DAG) production derived from phosphatidylinositol (4,5) bisphosphate, as indicated by the inhibition exerted by 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine and U-73122 (1-[6((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), which are pharmacological inhibitors of phosphoinositide-specific phospholipase C. In contrast, when HL-60 cells were induced to differentiate along the granulocytic lineage by dimethyl sulfoxide, we observed a rise in the nuclear DAG mass, which was sensitive to either neomycin or propranolol, two compounds with inhibitory effect on phospholipase D (PLD)-mediated DAG generation. In nuclei of dimethyl sulfoxide-treated HL-60 cells, we observed a rise in the amount of a 90-kDa PLD, distinct from PLD1 or PLD2. When a phosphatidylinositol (4,5) bisphosphate-derived DAG pool was generated in the nucleus, a selective translocation of PKC-beta II occurred. On the other hand, nuclear DAG derived through PLD, recruited PKC-alpha to the nucleus. Both of these PKC isoforms were phosphorylated on serine residues. These results provide support for the proposal that in the HL-60 cell nucleus there are two independently regulated sources of DAG, both of which are capable of acting as the driving force that attracts to this organelle distinct, DAG-dependent PKC isozymes. Our results assume a particular significance in light of the proposed use of pharmacological inhibitors of PKC-dependent biochemical pathways for the therapy of cancer disease.
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PMID:Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells. 1190 74

To check the anti-apoptosis gene bcl-2 protein/mRNA expression in 28 acute promyelocytic leukemia (APL), by immunohistochemistry and in situ hybridization, and to analyse the relationship among the bcl-2 gene expressions, clinical prognosis and classification of the isoforms of fuse gene in APL. The result shows the two types of isoforms of PML-RAR alpha have no significance in bcl-2 protein/mRNA expression, indexes of clinical prognosis. This shows that the classification of PML-RAR alpha isoform has no influence on clinical prognosis.
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PMID:[The relationship between clinical prognosis and classification of the isoforms of fuse gene in acute promyelocytic leukemia]. 1251 5