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)

Cells of the Abelson murine leukemia virus-transformed line L12 that lack the p53 protein also lack polyadenylated mRNA capable of directing the synthesis of p53 in a cell-free system. Direct analysis of stable polyadenylated mRNA from a variety of cell lines shows that all p53 producers shared a common mRNA species (2.0 kilobases) which hybridized with a p53-specific cDNA probe. This species, which appears to be the mature, normal-sized p53 mRNA, was totally undetectable in L12 cells, which did not produce p53 in vivo. However, L12 cells contained two major p53-specific mRNA species of a substantially larger size (3.5 and 6.5 kilobases) than the p53-specific mRNA in the p53-producing cells. Genomic DNA analysis uncovered an apparent alteration in the 5' proximal part of only one p53 gene, which is unique to the L12 cell line. It is thus possible that the nonproducer phenotype of L12 cells is due at least in part to an alteration within a p53-specific DNA sequence. These findings define a system in which production of p53 appears to be efficiently regulated at the level of stable mRNA and which can be used to study the mechanisms controlling p53 expression in Abelson murine leukemia virus-transformed cells.
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PMID:Abelson murine leukemia virus-transformed cells that lack p53 protein synthesis express aberrant p53 mRNA species. 614 42

Stage 1 (pre-malignant) and stage 2 (malignant) cells derived from mice infected with Friend murine leukemia virus or polycythemia-inducing Friend virus complex were examined and compared for the expression of a transformation-related cellular protein, p53. Stage 2 cells were found to express high levels of p53, whereas stage 1 cells did not express detectable levels of this protein. These results indicate that p53 may be a marker for transformed cells present in the second stage of diseases induced by Friend murine leukemia virus or polycythemia-inducing Friend virus complex.
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PMID:Expression of a transformation-related protein (p53) in the malignant stage of Friend virus-induced diseases. 634 27

The relationship between the expression of a transformation-related cellular-encoded phosphoprotein, p53, and the potential to form distant metastases was investigated in Abelson murine leukemia virus-transformed murine large cell lymphoma sublines of differing metastatic behaviors. Low metastasis RAW117-P and high metastasis RAW117-H10 cells were labeled with 35S-methionine, and several anti-p53 monoclonal antibodies were used to immunoprecipitate p53 from the cell lysates. Using these procedures, similar amounts of p53 were detected in the RAW117-P and -H10 cells. In addition, the expression of 2.0 Kb mRNA containing p53-specific sequences was equivalent in RAW117-P and -H10 cells. The results indicate that p53 expression, although apparently required for neoplastic transformation, is not quantitatively related to metastatic behavior in RAW117 large cell lymphoma cells.
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PMID:The expression of transformation-related protein p53 and p53-containing mRNA in murine RAW117 large cell lymphoma cells of differing metastatic potential. 639 97

Cultured cells from patients inheriting the rare cancer-prone and radiotherapy-sensitive disorder ataxia-telangiectasia (A-T) exhibit anomalies in cell cycle control and protein kinase C (PKC)-mediated upregulation of p53 protein following exposure to ionizing radiation. It remains unclear, however, as to whether this irregularity in a p53-dependent signal transduction pathway controlling the G1/S checkpoint is causally linked to the most consistent molecular hallmark of A-T-namely, marked attenuation in the inhibition of replicative DNA synthesis at early times (< or = 2 h) after irradiation [radioresistant DNA synthesis (RDS)]. We report here that treatment of normal human fibroblast strains with inhibitors of calmodulin (CaM) (i.e. W7 and W13) and CaM-dependent protein kinases II and IV (i.e. KN62) prior to radiation exposure elicits an 'A-T-like' RDS phenotype, whereas treatment with PKC inhibitors (e.g. staurosporine) does not produce this response. Moreover, at 1 h post-gamma irradiation A-T fibroblasts undergo normal induction of p53 protein while exhibiting the RDS trait. At later times (e.g. 4 h) following irradiation, however, these A-T cells contain abnormally low levels of p53 protein, as do their lymphoblastoid cell line counterparts during the entire post-gamma ray incubation period. On the other hand, human cells which either lack the p53 gene completely (i.e. HL60 leukemia cells) or harbor a germline mutation in the gene (i.e. Li-Fraumeni syndrome cells) shut down their DNA replication machinery normally upon sustaining radiation damage. We thus conclude that the transitory delay in DNA synthesis routinely experienced by human cells in the face of radiation injury is mediated through a CaM-dependent regulatory cascade which involves neither PKC nor p53 protein. Accordingly, A-T cells appear to be malfunctional in at least two distinct radiation-responsive signalling pathways, one regulating the G1/S checkpoint and governed by p53 and PKC and another controlling passage through S phase and requiring CaM.
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PMID:Characterization of the signal transduction pathway mediating gamma ray-induced inhibition of DNA synthesis in human cells: indirect evidence for involvement of calmodulin but not protein kinase C nor p53. 747 84

The induction of p53 by doxorubicin in normal human fibroblasts was completely reverted by TPA, a phorbol ester. A ts-p53 mutant protein which is ineffective at 37 degrees C, but behaves in a wild-type fashion at 32 degrees C, was overexpressed in the p53-null human leukemia cell line K562. Wild-type-p53 overexpression induced apoptosis, whereas TPA protected K562 cells from this phenomena. By analogy with the observed human fibroblasts, TPA was found to decrease p53 amount. The TPA-dependent down-regulation of p53 could explain the chromosomal gross alterations typical of cells subjected to a chronic TPA treatment, alterations also found in cells defective for p53 function.
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PMID:Phorbol esters attenuate the expression of p53 in cells treated with doxorubicin and protect TS-P53/K562 from apoptosis. 748 3

The human T-cell leukemia virus type I oncoprotein Tax transcriptionally deregulates a wide variety of viral and cellular genes. Tax deregulation of gene expression is mediated through interaction with a variety of structurally unrelated cellular transcription factors, as Tax does not bind DNA in a sequence-specific manner. Although most of these cellular transcription factors have been shown to mediate activation by Tax, we have recently demonstrated that members of the basic helix-loop-helix (bHLH) family of transcription factors, which play a critical role in progression through the cell cycle, mediate repression by Tax. In this report, we examined whether Tax might repress transcription of the tumor suppressor p53, as the p53 gene has recently been demonstrated to be regulated by the bHLH protein c-Myc. Furthermore, loss or inactivation of the p53 gene has been shown to be causally associated with oncogenic transformation. We show that Tax represses transcription of the p53 gene and that this repression is dependent upon the bHLH recognition element in the p53 promoter. Together, these results suggest that Tax may promote malignant transformation through repression of p53 transcription.
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PMID:Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. 749 59

Aggregation of the high affinity IgE receptors (Fc epsilon RI) on rat basophilic leukemia RBL-2H3 cells results in protein tyrosine phosphorylations. Previously we reported that there is prominent tyrosine phosphorylation of approximately 72-kDa proteins (pp72) and that the tyrosine kinase p72syk is one component of pp72. Here we studied further the relationship of p72syk to pp72. The aggregation of Fc epsilon RI induced the activation of p72syk which was parallel to its tyrosine phosphorylation. By in vitro kinase assay of immune complexes purified with anti-phosphotyrosine antibodies, p72syk was the major pp72 tyrosine kinase. However, by immunoblotting with anti-phosphotyrosine antibodies, p72syk was a minor component of pp72. The heterogeneous nature of pp72 was indicated by different studies. Under optimum conditions of one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, pp72 consisted of a heterogeneous group of 69-, 71-, and 72-kDa tyrosine-phosphorylated proteins. There were differences in the tyrosine phosphorylation of these proteins in cells activated in the absence of extracellular calcium or when stimulation was with the calcium ionophore A23187 or with phorbol myristate acetate. One of the proteins migrating at 69 kDa was p72syk. By two-dimensional gel electrophoresis pp72 was found to consist of multiple tyrosine-phosphorylated protens including 71-80-kDa proteins that associate with p53/56lyn. A 75-kDa tyrosine-phosphorylated protein, different from pp72, was identified as p75HS1 (SPY75). These results demonstrate the heterogeneous nature of the pp72 and that p72syk is activated after Fc epsilon RI aggregation.
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PMID:Activation of protein tyrosine kinase p72syk by Fc epsilon RI aggregation in rat basophilic leukemia cells. p72syk is a minor component but the major protein tyrosine kinase of pp72. 751 87

Disruption of normal p53 expression is the most frequent genetic change occurring in various human solid tumors; it is mostly due to sequence alterations of the p53 coding region by missense mutations or to loss of an entire, functional allele of this gene. In the present study, possible mechanisms resulting in a disruption of regulated expression of wild-type p53 were examined in acute leukemias of either lymphoid (ALL) or myeloid (AML) phenotype. p53 transcript accumulation, nucleotide sequence and gene structure were analyzed in primary leukemic cells from 50 patients. p53-specific transcripts were detected in 26/26 cases of ALL and 16/23 cases of AML using reverse transcriptase (RT)-PCR. Sequencing of transcripts did not reveal any point mutations or deletions. Heterozygosity at a polymorphic Bg/II site within intron 1 was found in 4/28 leukemic samples, and loss of one allele was noted in one of these. In addition, a novel, leukemia-associated structural abnormality located within the 5' flanking region of the p53 gene and associated with the loss of heterozygosity was observed in cells from this patient with ALL. The MDM2 gene which inactivates p53 by binding to it was neither amplified nor rearranged in 28 leukemias studied. Thus, disruption of regulated p53 expression resulting in lack of detectable p53 mRNA even by RT-PCR occurs in about 30% of cases of AML; however, p53 alterations typical for human solid tumors are an infrequent event in most types of human acute leukemias.
Leukemia 1994 Oct
PMID:Mechanisms of p53 alteration in acute leukemias. 752 98

Aggregation of the receptor with high affinity for IgE (Fc epsilon RI) on the surface of mast cells and basophils stimulates phosphorylation of protein tyrosines, a process in which p53/56lyn kinase has been implicated. We measured the association between Fc epsilon RI and the kinase, using chemical crosslinking to stabilize their interaction. In the rat basophilic leukemia mast cell line, 3-4%, and at most 20%, of Fc epsilon RI appear to be associated with the kinase prior to aggregation, even though there is an excess of total cell lyn kinase. Aggregating the Fc epsilon RI causes three to four times more of the kinase to associate with receptors, a process requiring a prior phosphorylation step. In an in vitro assay, the lyn associated with the aggregated receptors becomes disproportionately more phosphorylated than would be predicted from the amount of lyn associated with the receptors. These and other data are consistent with a model in which aggregation of the receptor leads to its transphosphorylation by constitutively associated lyn kinase. We propose that additional molecules of this kinase are thereby recruited and that this markedly enhances transphosphorylation of tyrosine on the receptor and associated proteins, thereby initiating a cascade of further biochemical changes. This model is also consistent with data on receptors such as the clonotypic receptors on B and T lymphocytes, which share structural and functional features with Fc epsilon RI.
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PMID:Aggregation of the high-affinity IgE receptor and enhanced activity of p53/56lyn protein-tyrosine kinase. 752 94

We found three truncated p53 transcripts in a patient with chronic myelogenous leukaemia in blast crisis carrying chromosome 17 abnormalities. Sequencing of these transcripts revealed complete absence of the entire exons 7, 8 and 9 in one, exons 8 and 9 in another, and exon 10 in the other. Sequencing analysis of genomic DNA, however, revealed no mutation in exons 6-10 and their flanking introns. These results suggest that the aberrant p53 transcripts in this case might not result from splicing mutations but from an unknown affected splicing process.
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PMID:Multiple aberrant splicing of the p53 transcript without genomic mutations around exon-intron junctions in a case of chronic myelogenous leukaemia in blast crisis: a possible novel mechanism of p53 inactivation. 752 45


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