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)

Overexpression of the B cell leukemia/lymphoma-2 (bcl-2) gene has been shown to confer a survival advantage on cells by inhibiting apoptosis. In epithelia, the bcl-2 gene is also related to development and differentiation, and the protein is strongly expressed in the embryo in the epithelial cells of the developing mammary gland. To investigate directly the effect of bcl-2 on human epithelial cells, we used an amphotropic recombinant retrovirus to introduce the gene into nontumorigenic cell lines developed from luminal epithelial cells cultured from milk. Here we demonstrate that while bcl-2 overexpression does not directly induce the tumorigenic phenotype, it provides a survival advantage to the mammary epithelial cells by inhibiting cell death at confluence or under conditions of serum starvation, bcl-2 can also affect the phenotype of the original epithelial cells, and promote epithelial-mesenchymal conversion, accompanied by loss of the cell adhesion molecules E-cadherin and alpha 2 beta 1 integrin. The extent of the epithelial-mesenchymal conversion varies with small differences in the phenotype of the parental line and with the level of expression of Bcl-2 and in some cases cell lines emerge with a mixed phenotype. The increased survival of Bcl-2-expressing cells at confluence results in multilayering, and the development of three- dimensional structures. Where a mixed phenotype is observed these structures consist of an outer layer of polarized epithelial cells separated by a basement membrane-like layer from an inner mass of fibroblastoid cells. Branching morphogenesis of bcl-2 transfectants is also observed in collagen gels (in the absence of fibroblast growth factors). The results strongly indicate that by increasing their survival under restrictive growth conditions, and by modifying the epithelial phenotype, bcl-2 can influence the specific morphogenetic behavior of mammary epithelial cells.
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PMID:bcl-2 overexpression inhibits cell death and promotes the morphogenesis, but not tumorigenesis of human mammary epithelial cells. 777 80

Apoptotic cell death is an active process which regulates the maintenance of the hematopoietic homeostasis. It has been reported that wild-type p53 (wt-p53) protein induces apoptosis in leukemia cells. To assess whether p53 is involved in the apoptotic process of normal hematopoietic cells, we introduced the temperature-sensitive p53Val135 mutant into the murine myeloid precursor cell line 32Dcl3. These are diploid, non-tumorigenic cells whose survival and proliferation are dependent upon growth factor supply (IL-3 and serum). Overexpression of wt-p53 protein does not affect morphology and proliferation of 32D cells as long as they are maintained in the presence of IL-3. However, after IL-3 withdrawal, wt-p53 overexpression significantly accelerates apoptosis. This phenomenon is IL-3 specific since no differences in death rates induced by serum starvation are found between parental cells and p53-transfectants. When the latter experiments are carried out at 37 degrees C with p53 protein in mutant conformation, an extended survival of 32D cells is observed after IL-3 deprivation, but not after serum withdrawal. Taken together, these results show that wt-p53 actively mediates the apoptosis due to the absence of specific growth factors, such as IL-3, suggesting that p53 might be involved in the response of myeloid precursors to environmental cytokines for the maintenance of the hematopoietic homeostasis.
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PMID:Wild-type p53 modulates apoptosis of normal, IL-3 deprived, hematopoietic cells. 786 50

Daunorubucin (DNR) accumulation studies as functional tests of the multidrug resistance (MDR1) gene product P-glycoprotein have produced diverging results when correlated to response to chemotherapy in acute leukaemia. To investigate possible reasons for this diversity a starvation experiment, based upon prolongation of medium exchange, was set up in the multidrug resistant cell line CEM/VBL100. DNR accumulation (1 microgram/ml) was measured flow cytometrically in the presence or absence of Verapamil (10 micromol/l). In cells permanently kept under ideal growth conditions, addition of Verapamil resulted in an average 90% increase in DNR enhancement in five successive experiments. In contrast, DNR accumulation increased by only 26% when the medium exchange was prolonged by 30 h to 42 h. This effect was not accompanied by changes in the MDR1 gene expression at the RNA or protein level. Consequently, 53 leukaemic blast samples of 30 newly diagnosed and 18 relapsed or refractory patients with acute leukaemia (ALL-18, AML-37) were processed without any delay and under the most stringent conditions possible. Evidence of the classical MDR phenotype was arbitrarily defined by a greater than 20% enhancement in DNR accumulation in response to Verapamil (10 micromol/l) or Cyclosporin A (3 micromol/l). Using this cutoff point for analysis of newly diagnosed leukaemia we found DNR uptake better correlated to response to treatment (p = 0.002) than P-gp detection by means of immunocytochemistry, using a panel of monoclonal antibodies (p = 0.03). We conclude that DNR accumulation studies are a sensitive method for predicting therapy outcome in acute leukaemia when performed with necessary precautions.
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PMID:Prolongation of medium exchange is associated with a decrease in function but not expression of the P-glycoprotein pump in leukaemic cells. 859 88

The human leukaemia cell line KU812 has previously been used to study basophil differentiation. In this study the authors analysed the capacity of KU812 to produce the mast cell proteinase tryptase and to synthesize factor(s) mitogenic for fibroblasts. KU812 cells were treated with tetradecanoyl-phorbol-13-acetate (TPA), conditioned medium from the human T-cell line Mo (Mo-CM), or cultured under serum free conditions. After 4 days the cells were analysed for cell growth, differentiation, content of tryptase, and secretion of fibroblast mitogenic activity. Mo-CM and serum starvation increased the expression while TPA treatment down-regulated the expression of Fc epsilon RI-alpha chain. An increase in tryptase content in cell extracts was detected after 4 days of culture in serum-free medium or in the presence of Mo-CM. KU812 conditioned media was found to have a baseline expression of mitogenic activity on normal human foreskin fibroblasts that was increased after serum starvation or after treatment with TPA. Mast cell-derived tryptase has previously been reported to be mitogenic for fibroblasts, but in this study the expression of tryptase did not correlate with the expression of fibroblast mitogenic activity in KU812 cells. Furthermore, affinity-purified lung tryptase did not show any mitogenic activity. Platelet-derived growth factor was also excluded. Although the factor(s) from KU812 cells stimulating fibroblast proliferation have not been identified, our results indicate that basophils may be potential producers of growth factors inducing fibroblast proliferation.
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PMID:The fibroblast mitogenic activity released from human basophilic cell line KU812 is separate from tryptase and PDGF expression. 879 21

We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced the accumulation of daunomycin, another classic substrate of P-glycoprotein. Verapamil did not compete with the intracellular binding sites of vinblastine. In all these aspects, vinblastine behaved as a typical substrate of P-glycoprotein but verapamil did not. Our data suggest that verapamil is a reverser of P-glycoprotein but that its intracellular accumulation is not affected by this membrane-bound transporter.
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PMID:Drug accumulation in the presence of the multidrug resistance pump: dissociation between verapamil accumulation and the action of P-glycoprotein. 960 21

Polycystin, the PKD1 gene product mutated in autosomal dominant polycystic kidney disease, is a large membrane protein which is important in the differentiation of epithelial tubular structure. Furthermore, PKD1 mRNA is expressed in various tissues and in neoplastic cell lines particularly, suggesting that polycystin might be involved in differentiation and/or proliferation of other cell types. Therefore, in order to investigate such a possible role, polyclonal antibodies against a recombinant polycystin peptide were raised and used to study polycystin expression in human leukemia cell lines committed to differentiation. Using Western blot and laser scanning confocal microscopy analyses, we demonstrated expression of polycystin in erythroleukemia K562 cells as a membrane-associated polypeptide of approximately 450 kDa, mainly localized in cell-cell contacts. Protein size and subcellular distribution were similar to those found in the kidney epithelial KJ29 cell line. In addition, K562 cell erythroid differentiation induced by hemin was characterized by a reduction in polycystin expression, as measured by Western blot and Northern blot analyses. Cytofluorimetric analysis indicated that upon hemin treatment there was a progressive reduction in the number of polycystin-expressing cells as well as in proliferation rate. Furthermore, reduction in proliferating and polycystin-expressing cells was also observed in K562 cells after serum starvation. When serum was added to the serum-deprived cells an increase in cell number as well as in number of polycystin-positive cells was observed. In addition, polycystin, also expressed in promyelocytic leukemia HL60 cells, was downregulated when macrophage differentiation in HL60 was induced by TPA. Therefore, in these leukemic cells downregulation of polycystin appeared to be closely related to reduction in cell proliferation and to induction of differentiation. This suggests that polycystin may play a relevant role in these cell processes.
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PMID:K562 erythroid and HL60 macrophage differentiation downregulates polycystin, a large membrane-associated protein. 977 Mar 68

Severe weight loss associated with cancer continues to be a major cause of morbidity in cases of childhood malignancy. The etiology is not completely understood but is probably multifactorial, including reduced ingestion and altered metabolism of nutrients. Changes in the host metabolism of protein, fat and carbohydrate in the cancer-bearing host have been demonstrated both in animal models and in patients. Changes include increased protein turnover and loss of the normal compensatory mechanisms seen in starvation. Additionally, increased lipid breakdown results in depletion of lipid stores and changes in carbohydrate metabolism result in an energy-losing cycle. The increase in protein turnover seen in children with leukemia may be related to the tumor, the chemotherapy administered or to related conditions such as febrile neutropenia. The role of endogenous mediators of cancer cachexia has not yet been clearly elucidated, although tumor necrosis factor, interleukin I and interleukin 6 appear to be involved. Studies of energy expenditure in children with cancer have indicated that certain patients with a raised metabolic rate are at particular risk of severe weight loss. The challenge is to identify these vulnerable patients and to provide adequate nutritional support early in treatment and therefore avoid the deleterious effects of cachexia.
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PMID:Aspects of altered metabolism in children with cancer. 987 81

Exposure of the two related human leukemic cell lines U937 and TUR to chemotherapeutic compounds resulted in opposite effects on induction and resistance to apoptosis. Incubation of U937 cells with 1-beta-d-arabinofuranosylcytosine or the etoposide VP-16 was accompanied by growth arrest in G0/G1 of the cell cycle and an accumulation of a population in the sub-G1 phase which exhibited characteristics typical for the apoptotic pathway. In contrast, human TUR leukemia cells demonstrated no significant effects after a similar treatment with Ara-C and VP-16. Thus, TUR cells continued to proliferate in the presence of these anti-cancer drugs and the number of apoptotic cells as evaluated by propidium iodide staining and the detection of internucleosomal DNA fragmentation was significantly reduced when compared to the parental U937 cells. Similar effects were observed upon serum-starvation demonstrating resistance to apoptosis in TUR cells. Whereas induction of apoptosis is regulated by a network of distinct factors including the activation of proteolytically active caspases, we investigated these pathways in both cell lines. U937 cells demonstrated activation of the 32-kDa caspase-3 upon drug treatment by cleavage into the 20-kDa activated form. However, there was no 20-kDa caspase-3 fragment detectable in TUR cells. Simultaneously, the enzymatic activity of caspase-3 was significantly increased in drug-treated U937 cells as measured in vitro by enhanced metabolization of a fluorescence substrate and in vivo by cleavage of an appropriate substrate for caspase-3, namely, protein kinase Cdelta. In contrast, there was little if any caspase-3 activation detectable in drug-treated TUR cells. Taken together, these data suggest a signaling defect in the activation of the caspase-3 proteolytic system in TUR cells upon treatment with chemotherapeutic compounds which is associated with resistance to apoptosis in these human leukemia cells.
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PMID:Signaling defect in the activation of caspase-3 and PKCdelta in human TUR leukemia cells is associated with resistance to apoptosis. 1006 81

In the fission yeast Schizosaccharomyces pombe the nrd1(+) gene encoding an RNA binding protein negatively regulates the onset of differentiation. Its biological role is to block differentiation by repressing a subset of the Ste11-regulated genes essential for conjugation and meiosis until the cells reach a critical level of nutrient starvation. By using the phenotypic suppression of the S. pombe temperature-sensitive pat1 mutant that commits lethal haploid meiosis at the restrictive temperature, we have cloned ROD1, a functional homologue of nrd1(+), from rat and human cDNA libraries. Like nrd1(+), ROD1 encodes a protein with four repeats of typical RNA binding domains, though its amino acid homology to Nrd1 is limited. When expressed in the fission yeast, ROD1 behaves in a way that is functionally similar to nrd1(+), being able to repress Ste11-regulated genes and to inhibit conjugation upon overexpression. ROD1 is predominantly expressed in hematopoietic cells or organs of adult and embryonic rat. Like nrd1(+) for fission yeast differentiation, overexpressed ROD1 effectively blocks both 12-O-tetradecanoyl phorbol-13-acetate-induced megakaryocytic and sodium butyrate-induced erythroid differentiation of the K562 human leukemia cells without affecting their proliferative ability. These results suggest a role for ROD1 in differentiation control in mammalian cells. We discuss the possibility that a differentiation control system found in the fission yeast might well be conserved in more complex organisms, including mammals.
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PMID:Isolation of a mammalian homologue of a fission yeast differentiation regulator. 1020 6

Human T-cells immortalized (interleukin-2 [IL-2] dependent) by the human T-cell lymphotropic/leukemia virus type I (HTLV-I), in time, become transformed (IL-2 independent). To understand the biochemical basis of this transition, we have used the sibling HTLV-I-infected T-cell lines, N1186 (IL-2 dependent) and N1186-94 (IL-2 independent), as models to assess the responses to antiproliferative signals. In N1186 cells arrested in G1 after serum/interleukin-2 (IL-2) deprivation, downregulation of the cyclin E-CDK2 kinase activity correlated with decreased phosphorylation of CDK2 and accumulation of p27Kip1 bound to the cyclin E-CDK2 complex, as seen in normal activated PBMCs (peripheral blood mononuclear cells). In contrast, N1186-94 cells failed to arrest in G1 upon serum starvation, displayed constitutive cyclin E-associated kinase activity, and, although CDK2 was partially dephosphorylated, the amount of p27Kip1 bound to the complex did not increase. This observation, extended to two other IL-2-dependent as well as to three IL-2-independent HTLV-I-infected T-cell lines, suggests that the lack of cyclin E-CDK2 kinase downregulation found in the late phase of HTLV-I transformation may correlate with insufficient amounts of p27Kip1 associated with the cyclin E-CDK2 complex. Reconstitution experiments demonstrated that the addition of p27Kip1 to lysates from N1186-94 starved cells resulted in the downregulation of cyclin E-associated kinase activity supporting the notion that the unresponsiveness of the cyclin E-CDK2 complex to growth inhibitory signals may be due to inadequate amounts of p27Kip1 assembled with the complex in HTLV-I-transformed T-cells. In fact, the amount of p27Kip1 protein was lower in most HTLV-I-transformed (IL-2-independent) than in the immortalized (IL-2-dependent) HTLV-I-infected T-cells. Furthermore, specific inhibitors of the phosphatidylinositol 3-kinase (P13K) induced an increase of p27Kip1 protein levels, which correlated with G1 arrest, in both IL-2-dependent and IL-2-independent HTLV-I-infected T-cells. Altogether, these results suggest that maintaining a low level of expression of p27Kip1 is a key event in HTLV-I transformation.
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PMID:Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells. 1022 95


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