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 activity of the protein tyrosine kinase pp60c-src was determined for each of the 60 human cell lines in the panel used by the National Cancer Institute for the random screening of potential anticancer drugs. The leukemia, lymphoma, melanoma, and small-cell lung cancer derived cell lines had low pp60c-src activity. Surprisingly, non-small-cell lung and ovarian cell lines had a median pp60c-src activity which was greater than that of the panel of cells representing colon cancer, which is most often associated with elevated pp60c-src activity. This data defines homologous cell lines which contain low and high pp60c-src activity which will aid attempts to understand the role of this enzyme in human cancer.
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PMID:Activity of pp60c-src in 60 different cell lines derived from human tumors. 753 73

The c-src proto-oncogene encodes a M(r) 60,000 phosphoprotein, pp60c-src, with tyrosine-specific protein kinase activity. We have used an immune complex protein kinase assay for pp60c-src to analyze a spectrum of B-cell neoplasms. pp60c-src activity was elevated in all five hairy cell leukemia specimens and in a number of the large cell and immunoblastic lymphomas; neoplasms representing later stages in B-cell development. pp60c-src activity was low in neoplastic cells which correspond to early and intermediate stages in B-cell development (acute and chronic lymphatic leukemia, lymphoblastic lymphoma, small lymphocytic lymphoma). The enhanced pp60c-src activity was associated with high levels of pp60c-src protein. However, increased expression of c-src was not associated with amplification or gross structural rearrangement of the c-src gene. This preliminary study demonstrates elevated levels of pp60c-src protein and tyrosine protein kinase activity in neoplasms corresponding to the later stages of B-cell ontogeny.
Leukemia 1993 Sep
PMID:Increased expression of the src proto-oncogene in hairy cell leukemia and a subgroup of B-cell lymphomas. 769 Apr 41

We constructed a recombinant plasmid which expresses antisense src RNA after dexamethasone (Dexa) treatment, and transfected it into U937 human monoblastic leukemia cells (U937-ASRC). Induction of antisense src RNA expression diminished the amounts of c-Src and its protein tyrosine kinase (PTK) activity in U937-ASRC cells. The declines in c-Src and its PTK activity subsequently reduced the proliferation of U937-ASRC cells. To elucidate the growth signal transduction pathway downstream of c-Src, tyrosine phosphorylation of Shc was examined in U937-ASRC cells treated with Dexa. The decline in c-Src by induction of antisense src RNA expression decreased the level of tyrosine phosphorylation of Shc. Immunoprecipitated c-Src directly phosphorylated immunoprecipitated Shc on tyrosine residues in vitro. The amounts of Grb2 and Sos co-immunoprecipitated with Shc were decreased after Dexa treatment. However, the amount of Sos co-immunoprecipitated with Grb2 was apparently not affected by Dexa treatment. These results indicate that Grb2 and Sos constitutively associate with each other in U937 cells. Furthermore, the level of phosphorylation on tyrosine (204) essential for MAP kinase activation was decreased after Dexa treatment. Taken together with all these findings, it is suggested that c-Src directly phosphorylates Shc on tyrosine residues, which in turn binds to Grb2 constitutively associated with Sos to form a Shc-Grb2-Sos complex, and that the complex formation is coupled with MAP kinase activation mediated by Ras activation in U937 cells.
Leukemia 1997 Apr
PMID:Antisense src expression inhibits tyrosine phosphorylation of Shc and its association with Grb2 and Sos which leads to MAP kinase activation in U937 human leukemia cells. 909 89

Although the requirement for c-Src in extracellular matrix (ECM)-mediated fibroblast motility has been well established, the roles of hemopoietic Src family protein tyrosine kinases in leukocyte migration have not been fully elucidated. To address the issue, we analyzed fibronectin (Fn)-mediated adhesion signaling in rat basophilic leukemia (RBL) 2H3 cells overexpressing 1) Csk, 2) a membrane-anchored, gain-of-function Csk (mCsk), and 3) a kinase-defective mCsk (mCsk(-)). Parent RBL2H3 cells, expressing autoactivated c-kit, readily adhered to Fn-coated surface, developed typical leukocyte adhesion machinery (podosome), and migrated toward Fn without cytokine priming, thus provided a simple experimental system to analyze Fn-mediated outside-in signaling. While overexpression of Csk or the Csk mutants did not significantly affect cell adhesion to the Fn surface or alpha5 integrin recruitment to the attachment sites, Csk suppressed and mCsk almost abolished Fn-mediated tyrosine phosphorylation of paxillin, filamentous actin assembly to podosomes, and cell migration, but mCsk(-) did not. Coexpression of LynA devoid of C-terminal negative regulatory tyrosine in mCsk cells successfully restored Fn-mediated podosome formation and cell migration. Coexpression of c-Src lacking the C-terminal tyrosine reconstructed podosomes, but could not restore the cell migration regardless of its expression level. Collectively, these observations provide evidence that Src family protein tyrosine kinases are required, and that Lyn could transmit sufficient signal for Fn-mediated cytoskeletal changes leading to cell locomotion in RBL2H3 cells, and they suggest that Lyn and c-Src are differentially involved in cell motility.
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PMID:Essential roles of Lyn in fibronectin-mediated filamentous actin assembly and cell motility in mast cells. 975 94

Several lines of evidence suggest that the c-Src tyrosine kinase has a specific role in bone-resorbing osteoclasts. To investigate this further, we examined the expression of c-Src, its kinase family members, and their putative substrates in the human leukemia cell line FLG 29.1. Western blot analysis with specific antibodies against Src family members showed expression of Src, Fyn, and Lyn, lower levels of Yes and Hck, and the absence of Lck tyrosine kinase. During a 3-day treatment with phorbol 12-myristate, 13-acetate (PMA), which induces differentiation of FLG 29.1 cells toward an osteoclast-like phenotype, the levels of Src and Fyn increased and the levels of Lyn decreased. In a similar leukemia cell line, HL-60, Src protein was not constitutively expressed and not induced by PMA treatment, which leads to monocytic differentiation. PMA treatment of FLG 29.1 cells induced a strong increase in the expression of p120 Cbl and Pyk2 kinase, which are putative Src substrates. Pyk2 phosphorylation increased upon adherence of FLG 29.1 cells to fibronectin and to ST2 stromal cells. The expression of other Src substrates and interacting proteins, such as p120 Cas, p130 Cas, vinculin, Fak kinase, and the p85 phosphatidylinositol 3-kinase subunit either did not change or slightly increased during PMA treatment. The elevated total protein tyrosine phosphorylation in PMA-treated FLG 29.1 cells was abolished by herbimycin A, a Src inhibitor. These data are consistent with the proposed role of Src in the osteoclastic function and support the use of FLG 29.1 cells as a model to study Src substrates in the cells of the osteoclastic lineage.
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PMID:Expression of Src family kinases and their putative substrates in the human preosteoclastic cell line FLG 29.1. 984 6

The inherited or acquired deregulation of protein kinase activity has been implicated in the pathogenesis of many human diseases, including cancer. Therefore, the inhibition of kinases has been proposed to be a promising strategy in the context of anti-cancer treatment. Many other kinases have been selected as drug discovery targets based on the prevalence of mutations, over-expression and unscheduled activation in human cancer. Of the various protein kinases chosen, Src family kinases are amongst the most extensively studied kinase oncogenes in academia and industry. This review focuses on our current understanding of the deregulation and role of Src family kinases in human cancer and leukemia. Recent data implicate the action of c-Src in cancer metastasis, mediated by up-regulation of various protease systems (calpain, uPA) as well as disruption of E-cadherin signalling. Moreover, novel roles of various Src family members in the development of human leukemia have been found. New insights into downstream signalling mechanisms, including the activation of STAT3, PDK1 and Akt, further corroborate the importance of Src family kinases in tumorigenesis and chemoresistance. Despite our rather clear understanding of Src family kinases as pro-oncogenes no Src family kinase inhibitor has entered a clinical trial so far. This review will discuss prerequisites to be fulfilled for clinically targeting c-Src and its homologues using small molecule drugs.
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PMID:SRC family kinases: potential targets for the treatment of human cancer and leukemia. 1452 15

The hematopoietic-specific Galpha14 links a variety of G protein-coupled receptors to phospholipase Cbeta (PLCbeta) stimulation. Recent studies reveal that several Galpha subunits are capable of activating signal transducer and activator of transcription (STAT) proteins. In the present study, we investigated the mechanism by which Galpha14 mediates receptor-induced stimulation of STAT3. In human embryonic kidney 293 cells, coexpression of Galpha14 with delta-opioid receptor supported [D-Pen2, D-Pen5]enkephalin (DPDPE)-induced STAT3 phosphorylations at both Tyr705 and Ser727 in a pertussis toxin-insensitive manner. The constitutively active Galpha4QL mutant also induced STAT3 phosphorylations at these sites and promoted STAT3-dependent luciferase activity. Requirements for PLCbeta, protein kinase C (PKC), and calmodulin-dependent kinase II (CaMKII) in Galpha14QL-induced STAT3 activation were demonstrated by their respective inhibitors as well as by coexpression of their dominant-negative mutants. Inhibition of c-Src and Janus kinase 2 and 3 activities abolished STAT3 activation induced by Galpha14QL, but no physical association between Galpha14QL and c-Src could be detected by coimmunoprecipitation. Various intermediates along the extracellular signal-regulated kinase signaling cascade were apparently required for Galpha14QL-induced STAT3 activation; they included Ras/Rac1, Raf-1, and mitogen-activated protein kinase kinase-1/2. In contrast, functional blockade of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol-3 kinase had no effect on Galpha14QL-induced responses. PLCbeta, PKC, and CaMKII were shown to be involved in Galpha14QL-mediated c-Src phosphorylation. Similar results were obtained with human erythro-leukemia cells upon DPDPE treatment. These results demonstrate for the first time that Galpha14 activation can lead to STAT3 stimulation via a complex signaling network involving multiple intermediates.
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PMID:Signal transducer and activator of transcription 3 activation by the delta-opioid receptor via Galpha14 involves multiple intermediates. 1515 36

Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is characterized as an important enzyme for protecting cells from oxidative stress-induced apoptosis and regulating the production of leukotrienes and prostanoids in cells overexpressing PHGPx. We studied whether the expression level of PHGPx fluctuates in polymorphonuclear leukocytes (PMNs) which were exposed to reactive oxygen species (ROS) and inflammatory cytokines at an inflammation site. Human peripheral PMNs up-regulated the expression level of PHGPx following culture with TNF-alpha, but not with IL-1beta, IL-8, and GRO. The up-regulated PHGPx expression was also observed in neutrophil-like cells that differentiated from the human leukemia cell line HL60 only after stimulation with TNF-alpha. However, macrophage-like differentiated HL60 cells and other cell lines, A498, ECV304, HeLa, U937, and HEK293, showed no increase in the PHGPx expression. This up-regulation of PHGPx was inhibited by treatment with the anti-oxidants, pyrrolidine dithiocarbamate, and N-acetyl-L-cysteine, and by inhibitors of NFkappaB and Src kinases. The stimulation of neutrophil-like differentiated HL60 cells with TNF-alpha induced activation of NFkappaB and c-Src kinase, and the activation was attenuated by treatment with the anti-oxidants. Up-regulation in neutrophil-like HL60 cells was also observed following exposure to H(2)O(2). These results indicate that activation of NFkappaB and/or Src kinases through ROS signaling may be involved in the up-regulation of the PHGPx in human PMNs stimulated by TNF-alpha.
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PMID:Induction of phospholipid hydroperoxide glutathione peroxidase in human polymorphonuclear neutrophils and HL60 cells stimulated with TNF-alpha. 1622 6

Phospholipid scramblase 1 (PLSCR1) is a calcium-binding, multiply palmitoylated type II endofacial plasma membrane protein, while unpalmitoylated PLSCR1 protein can import into the nucleus, where it binds to genomic DNA. Although the original work showed that PLSCR1 contributes to the transbilayer movement of phospholipids, the following studies revealed that PLSCR1 expression can be induced by some cytokines such as interferon, epidermal growth factor, and also by leukemic cell differentiation-inducing agents such as all-trans retinoic acid (ATRA) and phorbol 12-myristate 13-acetate (PMA). PLSCR1 was also shown to interact with several protein kinases including c-Abl, c-Src, protein kinase Cdelta as well as some other proteins such as onzin, suggesting the roles of PLSCR1 in cell signaling. Indeed, the current evidence proposes that PLSCR1 contributes to cell proliferation, differentiation, apoptosis, and plays roles in the pathogenesis of cancers, especially leukemia.
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PMID:Phospholipid scramblase 1. 1717 84

At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.
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PMID:Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges. 1855 56


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