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)

The Notch genes of C. elegans, Drosophila melanogaster and vertebrates encode receptors responsible for cell fate decisions during development. These Notch receptors and their ligands, Delta and Jagged, have been implicated in several human diseases. Truncated, constitutively active mutant forms of the Notch receptor appear to be involved in human T-cell leukemia, mammary carcinomas in mice, and a tumorous germline phenotype in C. elegans. Since activated Notch induces solitary tumors in transgenic mice, it is highly likely that collaborating genetic events are required for tumor formation. We have assessed four signal transduction pathways to determine which might play additional roles in malignant transformation in concert with activated Notch4. Our results suggest that transformation by Notch does not, as might have been expected, depend on the Src-like kinases Lck and Fyn, nor upon signals from protein kinase A and C (PKA, PKC). Rather, transformation by Notch requires active signals from the Erk/MAP kinase and PI-3 kinase pathways downstream of Ras. Oncogene (2000) 19, 4191 - 4198
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PMID:Ras pathway signals are required for notch-mediated oncogenesis. 1098 May 92

The functional role of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1 in differentiation of human myelomonocytic leukemia cells (U937) exposed to low concentrations of the antimetabolite 1-beta-D-arabino-furanosylcytosine (ara-C) was examined utilizing a cell line stably expressing a p21CIP1 antisense construct. Continuous exposure to 50 nM ara-C led to marked induction of p21CIP1 at 48-72 h in empty-vector control cells but not in their antisense-expressing counterparts (p21AS/F4 and B8). Such treatment induced expression of the myelomonocytic differentiation marker CD11b in approximately 35% of control cells, but no evidence of maturation was noted in antisense-expressing lines. However, antisense-expressing cells exposed to low concentrations of ara-C exhibited a reciprocal increase in apoptosis, manifested by the appearance of cells with classic morphologic features and hypodiploid quantities of DNA, reduced mitochondrial membrane potential (deltapsim), an increase in cytochrome c release into the cytosol, cleavage/activation of procaspases-9 and -3, and degradation of PARP and p27Kip1. Whereas empty-vector control cells exposed to 50 nM ara-C exhibited a decline in Bcl-2 expression, dephosphorylation of pRb, and an initial accumulation in S-phase, antisense-expressing cells did not. However, c-Myc down-regulation induced by low concentrations of ara-C was, if anything, more complete in antisense-expressing cells. Exposure of control but not antisense-expressing cells to ara-C led to phosphorylation/activation of MAP kinase at 24 h; moreover, the specific MEK/MAP kinase inhibitor PD98059 enhanced low-dose ara-C-mediated apoptosis only in wild-type cells. Lastly, exposure to 50 nM ara-C for 72 h resulted in detectable levels of cytoplasmic p21CIP1, a phenomenon associated with resistance to apoptosis, only in empty vector controls. Collectively, these findings demonstrate a functional role for p21CIP1 in leukemic cell maturation induced by low concentrations of ara-C. They also indicate that, as in the case of more conventional differentiation-inducers such as phorbol esters, disruption of the p21CIP1 response after exposure to low concentrations of the cytotoxic drug ara-C prevents leukemic cells from engaging a maturation program, but instead directs them along an apoptotic pathway.
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PMID:Evidence of a functional role for the cyclin-dependent kinase inhibitor p21CIP1 in leukemic cell (U937) differentiation induced by low concentrations of 1-beta-D-arabinofuranosylcytosine. 1099 87

The effects of deregulated Raf activation on the growth and differentiation of hematopoietic cells were investigated. The cytokine-dependent murine myeloid FDC-P1 and human erythroleukemic TF-1 cell lines were transformed to grow in response to deregulated Raf expression in the absence of exogenous cytokines. The conditionally active Raf proteins were regulated by beta-estradiol as cDNAs containing the Raf catalytic, but lacking negative-regulatory domains, were ligated to the hormone binding domain of the estrogen receptor (deltaRaf:ER). Continuous deltaRaf expression prevented apoptosis in the absence of exogenous cytokines and altered the morphology of the FD/deltaRaf:ER cells as they grew in large aggregated masses (>100 cells) whereas the parental cytokine-dependent FDC-P1 cells grew in smaller grape-like clusters (< 10 cells). FD/deltaRaf-1:ER cells growing in response to Raf activation displayed decreased levels of the Mac-2 and Mac-3 molecules on their cell surface. In contrast, when these cells were cultured in IL-3, higher levels of these adhesion molecules were detected. Expression of activated Raf oncoproteins also abrogated cytokine dependency and prevented apoptosis of TF-1 cells. Moreover, the differentiation status of these Raf-responsive cells was more immature upon Raf activation as culture with the differentiation-inducing agent phorbol 12 myristate 13-acetate (PMA) and beta-estradiol resulted in decreased levels of the CD11b and CD18 integrin molecules on the cell surface. In contrast when the Raf-responsive cells were induced to differentiate with PMA and GM-CSF, in the absence of deltaRaf:ER activation, increased levels of the CD11b and CD18 molecules were detected. Retinoic acid (RA) inhibited 3H-thymidine incorporation in response to GM-CSF. Interestingly, Raf activation counterbalanced the inhibition of DNA synthesis caused by RA but not PMA. Thus deregulated Raf expression can alter cytokine dependency, integrin expression and the stage of differentiation. These Raf-responsive cell lines will be useful in elucidating the roles of the MAP kinase cascade on hematopoietic cell differentiation and malignant transformation.
Leukemia 2000 Nov
PMID:Effects of deregulated Raf activation on integrin, cytokine-receptor expression and the induction of apoptosis in hematopoietic cells. 1106 28

Cells sense and respond to extracellular factors via receptors on the cell surface that trigger intracellular signaling pathways. The signals received by the receptors on hematopoietic cells often determine if the cell proliferates, survives or undergoes apoptosis. Apoptosis can be induced by almost any cytotoxic stimuli. These stimuli may be an absence of signals arising from cellular receptors, stimulation of specific ligand receptors on the cell surface, chemotherapeutic agents, and ionizing radiation or oxygen radicals, as well as a number of other factors. Cellular kinases and phosphatases participate in signaling cascades that influence this process. We review the ability of the calmodulin-dependent-kinases, I-kappaB kinases, PI3-kinases, Jakkinases, PKC, PKA, and MAP kinase signaling pathways (Erk, Jnk, and p38), to influence the apoptotic process. In addition, we discuss the cross-talk that exists between signaling cascades that are pro-apoptotic and anti-apoptotic.
Leukemia 2000 Dec
PMID:Kinases: positive and negative regulators of apoptosis. 1118 89

The NPXXY motif (X represents any amino acid) in the seventh transmembrane domain of the chemotactic formyl peptide receptor (FPR) is highly conserved among G protein-coupled receptors. Recent work suggested that this motif contributes to G protein-coupled receptor internalization and signal transduction; however, its role in FPR signaling remains unclear. In this study we replaced Asn(297) and Tyr(301) in the NPXXY motif of the human FPR with Ala (N297A) and Ala/Phe (Y301A/Y301F), respectively, and determined the effects of the substitutions on FPR functions in transfected rat basophilic leukemia cells. Whereas all the mutant receptors were expressed on the cell surface, the N297A receptor exhibited reduced binding affinity and was unable to mediate activation of phospholipase C-beta and the p42/44 mitogen-activated protein kinase (MAP kinase). The Y301F receptor displayed significantly decreased ligand-stimulated internalization and MAP kinase activation, suggesting that the hydrogen bonding at Tyr(301) is critical for these functions. The Y301F receptor showed a chemotactic response similar to that of wild-type FPR, indicating that cell chemotaxis does not require receptor internalization and hydrogen bonding at the Tyr(301) position. In contrast, the Y301A receptor displayed a left-shifted, but overall reduced, chemotaxis response that peaked at 0.1-1 nM. Finally, using a specific MAP kinase kinase inhibitor, we found that activation of MAP kinase is required for efficient FPR internalization, but is not essential for chemotaxis. These findings demonstrate that residues within the NPXXY motif differentially regulate the functions of FPR.
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PMID:Differential roles of the NPXXY motif in formyl peptide receptor signaling. 1123 59

Mouse leukemia L1210 cells selected for resistance to deoxyadenosine contain ribonucleotide reductase that is not feedback inhibited by dATP. These deoxyadenosine-resistant cells (Y8) also do not express p53 protein but do have WAF1 and Gadd45 mRNA and protein. The Y8 cells show increased sensitivity to DNA damaging agents and kinase inhibitors. In these studies we show that in the presence of sodium salicylate (NaSal), the parental wild-type (WT) cells block in G2/M phase of the cell cycle while the Y8 cells show a marked increased in the G0/G1 population of cells. The Y8 cells are more sensitive to apoptosis induced by NaSal than the WT cells. NaSal treatment causes the induction of caspase-3-like activity in Y8 cells but no induction of caspase-3 activity in the WT cells. The caspase inhibitor, Ac-DEVD-CHO, decreased the percentage of Y8 cells in the early apoptotic fraction, but this decrease was reflected by an increase in the percent of cells in the late apoptotic/necrotic fraction. SB20358, a p38-MAP kinase inhibitor did not protect the Y8 cells from NaSal-induced apoptosis indicating that the p38-MAP kinase pathway was not involved in the NaSal-induced apoptotic pathway in the p53-independent Y8 cells.
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PMID:Increased sensitivity to sodium salicylate-induced apoptosis in drug-resistant leukemia L1210 cells. 1129 31

We examined the effects of cathepsin inhibitor 1 (CATI-1), a selective inhibitor of cysteine cathepsins, on human leukemia and lymphoma cells. CATI-1 induced apoptosis in all 12 cell lines tested. Apoptosis of CATI-1-treated leukemia/lymphoma cells was caspase-independent, p53-independent, BAX-independent as well as MAP kinase-independent. Our findings provide unprecedented experimental evidence that cathepsins play a pivotal role for the survival of human leukemia/lymphoma cells. Therefore, cathepsin inhibitors may provide the basis for new treatment programs against leukemia and lymphoma.
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PMID:Cathepsin inhibition induces apoptotic death in human leukemia and lymphoma cells. 1134 15

The Raf/MEK/MAP kinase cascade plays a critical role in transducing growth signals from activated cell surface receptors. Using deltaMEK1:ER, a conditionally active form of MEK1, we demonstrate the ability of this dual specificity protein kinase to abrogate the cytokine dependency of the murine lymphoid hematopoietic cell line FL5.12. Cytokine-independent cells were obtained from FL5.12 cells at a frequency of 1 x 10(-7), indicating that a low frequency of cells expressing deltaMEK1:ER were factor-independent. In general, cells that were converted to a cytokine-independent phenotype displayed a higher level of MAP kinase activity in response to deltaMEK1:ER activation than those that remained cytokine-dependent. deltaMEK1:ER-responsive cells could be maintained long-term in the presence of beta-estradiol, as well as the estrogen-receptor antagonist 4-hydroxy-tamoxifen. Removal of hormone led to the rapid cessation of cell growth in a manner similar to that observed when cytokine is withdrawn from the parental cells. GM-CSF mRNA transcripts were detected in the MEK1-responsive cells indicating that activated deltaMEK1:ER may induce a pathway leading to autocrine proliferation. Cytokine-dependent deltaMEK1:ER cells were found to increase the expression of GM-CSF receptor alpha (GM-CSFRalpha) in response to beta-estradiol. In contrast, MEK1-responsive cells were found to express constitutively lower levels of GM-CSFRalpha and beta common (betac) chains indicating that constitutive GM-CSF expression resulted in a decrease in GM-CSFR expression. Treatment of parental cells with supernatant from MEK1-responsive FL5.12 cells was sufficient to promote [3H]-thymidine incorporation. GM-CSF was found to enhance the viability of FL5.12 cells. The cell lines described here will be useful for elaborating the ability of the MAP kinase pathway to regulate cell proliferation in hematopoietic cells.
Leukemia 2001 May
PMID:Effects of inducible MEK1 activation on the cytokine dependency of lymphoid cells. 1136 41

Activation of the MEK/ERK/MAP kinase signaling pathway promotes the proliferation and survival of hematopoietic cells. The kinases MEK-1, MEK-2, ERK-1/MAPK and ERK-2/MAPK are activated by phosphorylation at specific sites, and these events can be monitored using phospho-specific antibodies. In this report we examined the importance of the MEK/ERK/MAP kinase pathway in the monocytic and granulocytic differentiation of myeloid cell lines. Induction of monocytic differentiation in HL-60 cells by treatment with phorbol 12-myristate 13-acetate (PMA) led to rapid and sustained activation of MEK-1/-2, ERK-1/MAPK and ERK-2/MAPK, while induction of granulocytic differentiation by retinoic acid (RA) caused similar activation of MEK-1/-2 and ERK-2/MAPK, but not ERK-1/MAPK. The total levels of these kinases were not affected during the course of differentiation along either pathway. Pretreatment of cells with 5 microM of the MEK-1/-2-specific inhibitor U0126 abrogated PMA- or RA-induced activation of ERK-1/MAPK and ERK-2/MAPK. Importantly, pretreatment of HL-60 cells with U0126 was found to potently inhibit both monocytic and granulocytic differentiation, as assessed by cytochemical staining for non-specific esterase or nitroblue tetrazolium reduction, flow cytometric analysis of myeloid surface markers, and immunoblotting for the cell cycle inhibitor p21 WAF1/Cip1. Similar results were seen in U937 cells, where U0126 inhibited PMA-induced monocytic differentiation, and in 32D cells, where G-CSF-induced granulocytic differentiation was inhibited by U0126 pretreatment. Additional experiments revealed that inhibition of MEK-1/-2 in HL-60 cells resulted in nearly complete inhibition of differentiation-induced cell death during monocytic differentiation. By contrast, U0126 only partially inhibited cell death resulting from granulocytic differentiation. Taken together, our findings demonstrate that the MEK/ERK/MAP kinase signaling pathway is activated, and plays a critical role, during both monocytic and granulocytic differentiation of myeloid cell lines.
Leukemia 2002 Apr
PMID:Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. 1196 Mar 50

We have used large-scale insertional mutagenesis to identify functional landmarks relevant to cancer in the recently completed mouse genome sequence. We infected Cdkn2a(-/-) mice with Moloney murine leukemia virus (MoMuLV) to screen for loci that can participate in tumorigenesis in collaboration with loss of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF. Insertional mutagenesis by the latent retrovirus was synergistic with loss of Cdkn2a expression, as indicated by a marked acceleration in the development of both myeloid and lymphoid tumors. We isolated 747 unique sequences flanking retroviral integration sites and mapped them against the mouse genome sequence databases from Celera and Ensembl. In addition to 17 insertions targeting gene loci known to be cancer-related, we identified a total of 37 new common insertion sites (CISs), of which 8 encode components of signaling pathways that are involved in cancer. The effectiveness of large-scale insertional mutagenesis in a sensitized genetic background is demonstrated by the preference for activation of MAP kinase signaling, collaborating with Cdkn2a loss in generating the lymphoid and myeloid tumors. Collectively, our results show that large-scale retroviral insertional mutagenesis in genetically predisposed mice is useful both as a system for identifying genes underlying cancer and as a genetic framework for the assignment of such genes to specific oncogenic pathways.
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PMID:Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. 1218 67


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