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)

A subline of Brown Norway (BN) acute myelocytic leukemia (AML) which can be propagated in suspension culture (designated IPC-81) is described. Injection into Lewis x BN F1 hybrid (LBN) rats resulted in a log-linear correlation between tumor cell dose and time till death from the onset of leukemia even after multiple (greater than 16) passages in vitro. An in vitro clonogenic assay for IPC-81 colony formation (CFU-leuk) was developed with excellent cloning efficiency (55-82%). Colonies grew without the addition of specific growth factors; syngeneic spleen-conditioned medium inhibited CFU-leuk by 40%, but co-culture with untreated normal LBN rat bone marrow cells had no effect on CFU-leuk. CFU-leuk could be detected in the bone marrow 7 to 10 days before morphologic detection of leukemia in injected animals. This cell line should prove useful in the preclinical evaluation of new strategies for treating AML and evaluating new bone marrow purging methods.
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PMID:A subline of the Brown Norway myeloid leukemia in the Lewis x Brown Norway rat: in vivo growth characteristics and development of an in vitro clonogenic assay. 278 72

We report a reproducible in vitro clonogenic assay for the transplantable BN rat promyelocytic leukemia (BNML). Colony growth required a feeder activity elaborated by normal rat marrow cells. This stimulating activity is ascribed to the stromal elements. The in vitro maintained BNML cell line IPC-81 [Lacaze et al., Leukemia Research 7, 145 (1983)] also exhibited stimulating activities at high cell concentrations, confirming the autocrine capacities previously described. The nature of the stimulating activity is unknown but it is probably not of CSF type, and is not transferred to culture supernatants. This in vitro clonal assay permits the quantification of the clonogenic cells present in leukemic marrow during the early stage of the disease, when BNML cells are not yet distinguishable morphologically. Leukemic Cell Forming Unit (L-CFU) response was linear; 5-10(3) clones can be scored reproducibly. The plating efficiency obtained with cultured IPC-81 cells was high (60-90%), whereas marrow transplanted leukemia cells had reduced clonogenic capacities. These results are discussed.
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PMID:Evaluation of the clonogenic cell population (Leuk-CFU) in the marrow of BN rats during development of a promyelocytic leukemia (BNML): an in vitro assay. 658 62

Two murine cell lines, L1210 leukemia (T-cell) and B16 melanoma, and 3 human cell lines, CCRF-CEM leukemia (T-cell), NC37 lymphoblasts (B-cell) and IPC-48 melanoma were compared with respect to sensitivity to N-(phosphonacetyl)-L-aspartate (PALA), growth rate and aspartate transcarbamylase activity. No correlation between drug sensitivity and growth rate was found. The melanoma cell lines were more sensitive to PALA than were the lymphocytic cell lines. The 2 T-cell leukemia lines had similar sensitivities to PALA while the B-lymphoblasts were more resistant at 10(-3) M PALA and less resistant at 10(-4) M PALA than were L1210 and CCRF-CEM cells. Aspartate transcarbamylase activity was similar among the 2 melanoma cell lines and among the 3 lymphocytic cell lines and was 2-fold higher in the latter.
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PMID:Inhibition of cell growth by N-(phosphonacetyl)-L-aspartate in human and murine cells in vitro. 727 1

Novel (Rp)-cAMPS analogs differed widely in ability to antagonize cAMP activation of pure cAMP-dependent protein kinase I and II and to antagonize actions of cAMP on gene expression, shape change, apoptosis, DNA replication, and protein phosphorylation in intact cells. These differences were related to different abilities of the analogs to stabilize the holoenzyme form relative to the dissociated form of cAMP kinase type I and II. (Rp)-8-Br-cAMPS and (Rp)-8-Cl-cAMPS were the most potent cAMP antagonists for isolated type I kinase and for cells expressing mostly type I kinase, like IPC-81 leukemia cells, fibroblasts transfected with type I regulatory subunit (RI), and primary hepatocytes. It is proposed that (Rp)-8-Br-cAMPS or (Rp)-8-Cl-cAMPS should replace (Rp)-cAMPS as the first line cAMP antagonist, particularly for studies in cells expressing predominantly type I kinase. The phosphorylation of endogenous hepatocyte proteins was affected oppositely by (Rp)-8-Br-cAMPS and increased cAMP, indicating that (Rp)-8-Br-cAMPS inhibited basal cAMP-kinase activity. The inhibition of basal kinase activity was accompanied by enhanced DNA replication, an effect which could be reproduced by microinjected mutant cAMP-subresponsive RI. It is concluded that the basal cAMP-kinase activity exerts a tonic inhibition of hepatocyte replication. (Rp)-8-Br-cAMPS and microinjected RI also desensitized hepatocytes toward inhibition of DNA synthesis by interleukin-1 beta. This indicates that basal cAMP-kinase activity can have a permissive role for the action of another (interleukin-1 beta) signaling pathway.
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PMID:Novel (Rp)-cAMPS analogs as tools for inhibition of cAMP-kinase in cell culture. Basal cAMP-kinase activity modulates interleukin-1 beta action. 765 38

cAMP induced rapid apoptosis (> 90% cell death in 6 h) of non-growth-arrested rat leukemia IPC-81 cells. A cell clone selected for cAMP resistance had a normally functioning apoptotic machinery whose triggering required about 30-fold higher cellular cAMP than in the parent cells. The cAMP subresponsiveness was due to a heterozygous point mutation (Ala336-->Asp) in the RI subunit of cAMP-dependent protein kinase I. In fact, apoptosis correlated with intracellular cAMP binding to the subresponsive RI. The mutated alanine is invariantly present in cyclic nucleotide kinases, but of unknown function. The mutation decreased the cAMP affinity to site B by increasing the cAMP dissociation rate 500x. The ability of site B to discriminate adenine-modified cAMP analogues was affected, suggesting that Ala336 faced the adenine moiety of cAMP. That the heterozygously expressed RID336 was a dominant suppressor of apoptosis was explained by a higher expression of R than C subunits in the mutant cells by preferential expression of the mutant form of RI, and by the ability of mutant RI to exert dominant negative control of activation of wild type cAMP kinase at moderate cAMP levels. Apoptosis was induced at a similar cAMP level in cells treated with cholera toxin or other cAMP elevating agents, indicating that cAMP kinase was essential for toxin action.
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PMID:Antiapoptotic effect of heterozygously expressed mutant RI (Ala336-->Asp) subunit of cAMP kinase I in a rat leukemia cell line. 838 40

Rat IPC-81 promyelocytic leukemia cells responded to cAMP analog by undergoing apoptotic cell death both when anchored to fibronectin and when free in the medium. The protein kinase C stimulator 12-O-tetradecanoylphorbol 13-acetate enhanced the anchoring to substratum without impeding cAMP-induced cell death. The immobilized cells could be microinjected. This made it possible to study the effect on apoptosis of microinjected catalytic (C alpha) and regulatory (RI alpha D199) subunits of cAMP-dependent protein kinase as well as of phosphatase inhibitors. Microinjection of C alpha reproduced the morphological effects of cAMP, including nuclear fragmentation. RI alpha D199 blocked the effect of C alpha. Injection of microcystin-LR, which inhibits protein phosphatases 1 and 2A, led to pronounced apoptoid changes of the leukemia cells, but failed to produce nuclear fragmentation. Microinjection of peptide inhibitors ("inhibitor 1" and "inhibitor 2") specific for phosphatase 1 had no effect on cell morphology. The failure of the phosphatase inhibitors to reproduce completely the effect of the C subunit underscores the specificity of action of the latter.
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PMID:Microinjected catalytic subunit of cAMP-dependent protein kinase induces apoptosis in myeloid leukemia (IPC-81) cells. 838 20

The cAMP pathway plays a central role in the response to hormonal signals for cell proliferation, differentiation and apoptosis. In IPC-81 leukaemia cells, activation of the cAMP pathway by prostaglandin E1 treatment, or other cAMP-elevating agents, induces apoptosis within 4-6 h. Inhibition of mRNA or protein synthesis during the first 2 h of cAMP induction protects cells from apoptosis, suggesting a requirement for early gene expression. cAMP-dependent protein kinase phosphorylates a class of nuclear factors and thereby regulates the transcription of a specific set of genes. Here we show that CREM (cAMP Responsive Element Modulator) expression is induced rapidly upon prostaglandin E1 treatment of IPC-81 cells. The induced transcripts correspond to the early product ICER (Inducible cAMP Early Repressor). ICER expression remains elevated until the burst of cell death. Protein synthesis inhibitors which prevent cAMP-induced apoptosis also block de novo ICER synthesis. Transfected IPC-81 cell lines, constitutively expressing high level of ICER are resistant to cAMP-induced cell death. In these transfected cells, cAMP fails to upregulate the ICER transcripts demonstrating that ICER exerts strongly its repressor function on CRE-containing genes. That an early expression of ICER blocks apoptosis, suggests that gene repression by endogenous ICER in IPC-81 is insufficient or occurs too late to protect cells against death. ICER transfected cells rescued from cAMP-induced apoptosis are growth arrested. It shows for the first time that CREM activation directly participates to the decision of the cell to die. ICER, by sequentially repressing distinct sets of CRE-containing genes could modulate cell fate.
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PMID:The transcriptional repressor ICER and cAMP-induced programmed cell death. 926 69

An elevated cAMP concentration results in growth arrest and protein synthesis-dependent apoptosis in the promyelocytic leukaemia cell line IPC-81. A comparison of two-dimensional gels of extracts from these cells labelled with [(35)S]methionine revealed that five distinct protein spots were induced by cAMP in a protein-synthesis-dependent manner. The spots seemed to result from the acidic shift of a precursor protein. The most abundant spot was phospho-actin. The spots induced by cAMP in intact cells were induced by cAMP-dependent protein kinase (cAPK) during the translation in vitro of mRNA from the leukaemia cells. The effect of cAPK was strictly co-translational, none of the spots being induced when cAPK was added after translation. This suggested that the protein spots arose by co-translational phosphorylation catalysed by cAPK. Two of the protein spots, phospho-actin and a protein with a molecular mass of 30 kDa and an isoelectric point of 4.5, were studied further with respect to expression. They were produced during the whole pre-apoptotic period, had cellular half-lives of several hours and were induced by the same concentrations of cAMP analogue that induced apoptosis. It is suggested that the accumulation of co-translationally modified proteins could be important for long-term cAMP signalling.
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PMID:cAMP induces co-translational modification of proteins in IPC-81 cells. 1045 24

The IPC-81 myeloid leukaemia cells undergo apoptosis rapidly after cAMP stimulation (6 h) and cell death is prevented by early over-expression of the cAMP-inducible transcription repressor ICER, that blocks cAMP-dependent nuclear signalling. Therefore, the expression of specific genes controlled by CRE-containing promoters is likely to determine cell fate. We now show that cAMP-induced cell death also is abrogated by the over-expression of the anti-apoptotic gene, Bcl-2. Contrary to ICER, Bcl-2 does not affect cAMP-signalling and allows the analysis of cAMP responses in death rescued cells. The Bcl-2 transfected cells treated with 8-CPT-cAMP were growth-arrested and thereafter cells embarked in granulocytic differentiation, with no additional stimulation. Neutrophilic polynuclear granulocytes benefited from a long life span in G0-G1 and remained functional (phagocytosis). This work demonstrates that, using anti-apoptosis regulators, 'death signals' could be exploited to trigger distinct biological responses. Indeed, cAMP signal can trigger several simultaneously developing biological programs, in the same cell, i.e., growth regulation, apoptosis and differentiation. This cell system should prove useful to determine how a tumour cell can be re-programmed for either apoptosis or functional maturation by physiological signals.
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PMID:Ectopic expression of Bcl-2 switches over nuclear signalling for cAMP-induced apoptosis to granulocytic differentiation. 1113 82

It is well known that hyperthermia causes a transient tolerance of cells to a second heat challenge (acquired thermotolerance). The present study addresses the question of whether hyperthermic pre-treatment also increases the tolerance against heat- and hydrogen peroxide-induced apoptosis in rat IPC-81 leukaemia cells. This cell line exhibits an aberrant heat shock response which is characterized by a lack of the inducible Hsp70 isoform, even under conditions of heat or hydrogen peroxide stress, while the constitutively expressed Hsc70 and the inducible isoform of hemoxygenase (HO-1) are strongly enhanced by heat stress (43.5 degrees C; 30 min). In spite of this Hsp70 deficiency, hyperthermic pre-treatment protects IPC-81 leukaemia cells against apoptotic cell death induced by heat or hydrogen peroxide, but is less effective against necrosis induced by higher doses of the applied stressors. Addition of hydrogen peroxide (25 microM) enhances the amount of bax mRNA, while the level of bcl-2 mRNA remains unchanged. No increase of bax mRNA, in contrast, could be detected in heat shock-primed IPC-81 cells when treated with hydrogen peroxide after a 12h recovery. These results indicate that hyperthermic pre-treatment may exert its anti-apoptotic function not only by enhanced expression of constitutive as well as inducible HSPs but also by lowering the level of bax transcripts and thereby increasing the Bcl-2/Bax ratio.
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PMID:Hyperthermic pre-treatment protects rat IPC-81 leukaemia cells against heat- and hydrogen peroxide-induced apoptosis. 1207 89


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