Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signalling proteins such as phospholipase C-gamma (PLC-gamma) or GTPase-activating protein (GAP) of ras contain conserved regions of approximately 100 amino acids termed src homology 2 (SH2) domains. SH2 domains were shown to be responsible for mediating association between signalling proteins and tyrosine-phosphorylated proteins, including growth factor receptors. Nck is an ubiquitously expressed protein consisting exclusively of one SH2 and three SH3 domains. Here we show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues. Similar stimulation of Nck phosphorylation was detected upon activation of rat basophilic leukemia RBL-2H3 cells by cross-linking of the high-affinity immunoglobulin E receptors (Fc epsilon RI). Ligand-activated, tyrosine-autophosphorylated platelet-derived growth factor or epidermal growth factor receptors were coimmunoprecipitated with anti-Nck antibodies, and the association with either receptor molecule was mediated by the SH2 domain of Nck. Addition of phorbol ester was also able to stimulate Nck phosphorylation on serine residues. However, growth factor-induced serine/threonine phosphorylation of Nck was not mediated by protein kinase C. Interestingly, approximately fivefold overexpression of Nck in NIH 3T3 cells resulted in formation of oncogenic foci. These results show that Nck is an oncogenic protein and a common target for the action of different surface receptors. Nck probably functions as an adaptor protein which links surface receptors with tyrosine kinase activity to downstream signalling pathways involved in the control of cell proliferation.
 ...
PMID:The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors. 133 47

A series of flavones has been prepared, which are variously substituted in the 3,3',4',5 and 7 positions with halo-, alkoxy-, nitro-, amino-, hydroxy-, acyloxy- and azido-groups, for evaluation of their cytotoxicity to ANN-1 cells (3T3 murine fibroblasts transformed with the Abelson murine leukaemia virus) which contain a tyrosine kinase. This cytotoxicity was compared to their non-transformed 3T3 counterparts. 3'-Amino-4'-methoxyflavone was the most cytotoxic compound (IC50 = 1.6 microM) and was less inhibitory to the non-transformed parent 3T3 cell line (IC50 = 8 microM). The compound was inactive at 50 microM in assays of the inhibition of the cell-associated Abelson protein tyrosine kinase but inhibited an epidermal growth factor (EGF) protein tyrosine kinase by 42% at 50 microM. Quercetin (3,3',4',5,7-pentahydroxyflavone) was the most potent inhibitor of the Abelson protein tyrosine kinase but showed no selective inhibition of the growth of ANN-1 cells compared to the parent 3T3 cell line. Different structure-activity relationships were observed between the results of the cytotoxicity assays and inhibition of protein tyrosine kinases. Inhibitors of the Abelson protein tyrosine kinase which were competitive with respect to ATP showed different potencies for inhibition of the EGF receptor kinase.
 ...
PMID:Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases. 138 29

Activation of receptor-linked and cytoplasmic protein tyrosine kinases is crucial in the control of normal and abnormal cell growth and differentiation. Some substrates of protein tyrosine kinases such as phospholipase C gamma and ras GTPase-activating protein (GAP) contain sequences homologous to the src protein domains SH2 and SH3 (refs 3-9). The proto-oncogene vav is expressed in haematopoietic cells and its product Vav contains sequence motifs commonly found in transcription factors, such as helix-loop-helix, leucine-zipper and zinc-finger motifs and nuclear localization signals, as well as a single SH2 and two SH3 domains. Here we show that stimulation of T-cell antigen receptor on normal human peripheral blood lymphocytes or on human leukaemic T cells, and the crosslinking of IgE receptors on rat basophilic leukaemia cells, both promote the phosphorylation of tyrosine residues in Vav. Moreover, activation of the receptor for epidermal growth factor leads to marked tyrosine phosphorylation of Vav in cells transiently expressing vav, and Vav associates with the receptor through its SH2 domain. We propose that vav encodes a new class of substrates whose tyrosine phosphorylation may provide a mechanism for direct signal transduction linking receptors at the cell surface to transcriptional control.
 ...
PMID:Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. 161 45

To test the feasibility of using the human epidermal growth factor receptor (EGFR) as a model for growth factor receptor action in human hematopoietic cells, we infected Burkitt lymphoma cells (Namalwa) with a recombinant amphotrophic retrovirus containing a thymidine kinase promoter-driven human EGFR complementary DNA and the neomycin resistance gene. Neomycin-resistant cells expressing surface EGFR were selected by cell sorting using anti-EGFR monoclonal antibody 225. The selected cells expressed a Mr 170,000 protein immunoprecipitated by monoclonal antibody 225 and apparently identical to EGFR from A431 carcinoma cells. Infected Namalwa cells expressed 42,000 epidermal growth factor (EGF) binding sites/cell, and Scatchard analysis showed two affinities (Kd approximately 5 nM and approximately 0.5 nM). EGFR autophosphorylation was detected using antiphosphotyrosine antibodies after 5 min exposure to EGF. EGF binding induced rapid EGFR internalization (t1/2 = 9 min) and mobilization of transferrin receptors to the cell surface within 1 min. In fetal bovine serum-containing and serum-free cultures, EGF did not stimulate Namalwa cell proliferation. However, in the presence of 1.25% dimethyl sulfoxide (DMSO), EGF caused a dose-dependent increase in DNA synthesis. DMSO induced a cell cycle block in G1, which was partially reversed by EGF. DMSO induced changes in some B-cell markers suggesting cellular differentiation and increased surface EGF receptor number. Cells grown in DMSO and EGF were established as an EGF-dependent cell line for greater than 12 weeks, whereas cells grown in DMSO without EGF died within 1-2 weeks. Namalwa cells expressing EGFR demonstrated more rapid tumor growth in athymic mice. These studies demonstrate expression of functional EGFR mediating early biochemical and growth responses in a human hematopoietic cell, and indicate that EGFR can be used as an effective model in human hematopoietic cells. Results using DMSO are consistent with studies in other human leukemia cells indicating that agents inducing differentiation can restore growth factor dependence in previously factor-independent leukemia cells.
 ...
PMID:Expression of functional epidermal growth factor receptors in a human hematopoietic cell line. 170 31

Nicotinamide methyltransferase (Nmd CH3transferase) activity increased in the liver of mice after i.p. transplantation of Ehrlich ascites tumor (ascitic form), but not in the liver of mice with acute inflammation induced by the i.p. administration of D-galactosamine, and it rather showed a decrease together with necrosis after carbon tetrachloride administration. When Nmd CH3transferase activity of rat hepatocytes in primary culture was investigated with the addition of dexamethasone, epidermal growth factor, transforming growth factor-beta, tumor necrosis factor-alpha and N1-methylnicotinamide (1-CH3Nmd), changes in activity were not correlated with DNA synthesis, suggesting that the increase of this enzyme activity in the tumor host liver was not directly related to liver cell proliferation. Thus, in order to make use of the increase of this enzyme activity as a tumor burden marker, a procedure for its estimation by measuring the blood level of 1-CH3Nmd, a metabolite of Nmd produced by Nmd CH3transferase, was established. The 1-CH3Nmd level in the blood of mice bearing Ehrlich ascites tumor 4 h after s.c. loading of Nmd (500 mg/kg body weight) was closely correlated with this enzyme activity in the liver (r = 0.835, P less than 0.00001) from the early to the terminal stage of tumor development. Furthermore, similar correlations were seen in the animal groups bearing various other tumors, such as s.c. implanted Ehrlich ascites tumor (solid form) and i.p. implanted sarcoma S-180, hepatoma MH-134, Yoshida ascites sarcoma and leukemia L-1210, but not solid tumors such as Lewis lung carcinoma and melanoma B-16, although almost all of the animals bearing these tumors showed a higher enzyme activity than their control normal animals.
 ...
PMID:N1-methylnicotinamide level in the blood after nicotinamide loading as further evidence for malignant tumor burden. 183 57

The CD45 antigen cluster identifies a family of transmembrane glycoprotein tyrosine phosphatases (PTPases) present on nearly all hemopoietic cells. Recent studies suggest that CD45 may play a role in the control of receptor mediated blood cell responses, and that expression of the CD45 gene varies during bone marrow cell maturation. However, relatively little is known of the mechanisms controlling CD45 expression and function. Here we show that the induction of granulocyte or monocyte differentiation of HL60 leukemia cells is accompanied by a rapid increase in CD45 antigen expression and CD45 PTPase activity. In contrast, other leukemia cell lines induced for monocyte/macrophage differentiation did not show increased CD45. Immunoprecipitation of radiolabelled CD45 glycoprotein from dimethyl sulphoxide (DMSO) treated HL60 cells indicated that the cells expressed 200 and 180 kD isoforms. Northern blots of steady-state RNA from HL60 cells showed a 4-11-fold increase in CD45 transcripts after DMSO treatment, but no alteration in the half-life of CD45 mRNA. Nuclear transcription assays showed that CD45 expression was controlled at the level of gene transcription. Namalwa Burkitt leukemia cells expressing the heterologous epidermal growth factor (EGF) receptor protein tyrosine kinase were used to assess the specificity of CD45 PTPase activity. Co-clustering of CD45 and the EGF receptor with specific monoclonal antibodies failed to alter the EGF stimulated tyrosine phosphorylation of the EGF receptor. These studies indicate that CD45 increases during myeloid maturation, and the expression of the CD45 gene is controlled at the level of gene transcription. Preliminary studies suggest that CD45 does not alter the protein tyrosine kinase activity of the EGF receptor in intact cells, suggesting substrate specificity in vivo.
Leukemia 1991 Apr
PMID:Regulation of CD45 expression in human leukemia cells. 185 Dec 41

Sodium vanadate (11 microM) amplified the PGI2 production of rat liver cells (the C-9 cell line) incubated with thrombin, platelet activating factor, lysine-vasopressin, the Ca2(+)-ionophore A-23187, interleukin-1 beta, 12-tetradecanoylphorbol-13-acetate, teleocidin, epidermal growth factor, palytoxin, thapsigargin and colchicine but not that stimulated by exogenous arachidonic acid. Sodium vanadate (2.2 microM) also amplified PGF2 alpha production of dog kidney cells (the MDCK cell line) incubated with norepinephrine and, at 0.4 microM, PGI2 production of bovine aorta smooth muscle cells stimulated by serotonin. Sodium vanadate (55 microM) did not affect production of PGE2 and PGF2 alpha in rat basophil leukemia cells (the RBL-1 cell line) stimulated by the Ca2(+)-ionophore A-23187, but did inhibit synthesis of peptide-containing leukotrienes and 12-hydroxyeicosatetraenoic acid. When used with cultured cells at micromolar concentrations, vanadate is known to inhibit protein tyrosine-phosphate phosphatases. These results suggest that in some cells deesterification of lipids is positively regulated, at least in part, by phosphorylation of tyrosine whereas in leukocytes, lipoxygenase activities are negatively regulated, at least in part, by phosphorylation of tyrosine.
 ...
PMID:Actions of vanadate on arachidonic acid metabolism by cells in culture. 202 Jul 48

The BCL2 (B cell lymphoma/leukemia-2) proto-oncogene encodes a 26-kDa protein that has been localized to the inner mitochondrial membrane and that has been shown to enhance the survival of some types of hematopoietic cells. Here we show that NIH3T3 fibroblasts stably transfected with a BCL2 expression plasmid exhibit reduced dependence on competence-inducing growth factors (platelet-derived growth factor, PDGF; epidermal growth factor, EGF) for initiation of DNA synthesis. The importance of BCL2 for growth factor-induced proliferation of these cells was further confirmed by the useage of BCL2 antisense oligodeoxynucleotides. The mechanisms by which overexpression of p26 BCL2 contributes to fibroblast proliferation are unknown, but do not involve alterations in: (a) the production of inositol triphosphates (IP3), (b) PDGF-induced transient elevations in cytosolic Ca2+ ions, or (c) the activity of protein kinase C enzymes in these transfected cells. The results imply that changes in mitochondrial functions play an important role in the early stages of the cell cycle that render 3T3 cells competent to respond to the serum progression factors that stimulate entry into S-phase.
 ...
PMID:Mitochondrial protein p26 BCL2 reduces growth factor requirements of NIH3T3 fibroblasts. 207 Aug 13

To determine the effect of oncogene expression on gamma radiation sensitivity of hematopoietic compared to fibroblastic cells, we selected clonal sublines of an interleukin-3 (IL-3)-dependent hematopoietic progenitor cell line 32D cl 3 and NIH/3T3 embryo fibroblastic cells following transfection with each oncogene linked to the mycophenolic acid resistance gene. Each mycophenolic acid-resistant subclone demonstrated high levels of specific poly(A)+ mRNA for each oncogene. The parent line 32D cl 3 demonstrated similar radiosensitivity at 116 cGy/min (D0 126, n 1.17) compared to 5 cGy/min (D0 123, n 1.65). This pattern was not altered in subclones of 32D cl 3 cells transfected with the epidermal growth factor (EGF) receptor gene and grown in EGF (at 116 cGy/min D0 104, n 0.998, at 5 cGy/min D0 115, n 1.09), or in 32D cl 3 cells expressing the v-sis oncogene (at 116 cGy/min D0 122.4, n 1.79, at 5 cGy/min D0 135, n 1.43). In contrast, expression of the transfected oncogenes v-erb-B, v-abl, or v-src conferred significant radioresistance at 5 cGy/min dose rate (D0 194, n 1.77; D0 165.5, n 1.56; D0 171, n 1.28, respectively). With the exception of v-sis, oncogene expression resulted in nonautocrine factor independence of 32D cl 3 subclones, and production of donor origin tumors in syngeneic new-born or adult mice. Two rare spontaneous factor-independent subclones of 32D cl 3 were also tested. Nonautocrine clone 32D cl 2 demonstrated significantly increased radioresistance at low dose rate (D0 186, n 1.63), while autocrine (IL-3 producing) subclone 32D cl 4 revealed no significant increase in radioresistance at 5 cGy/min. The parent fibroblast cell line NIH/3T3 showed an intrinsic relative radioresistance at low dose rate (at 5 cGy/min D0 157.3, n 1.81, compared to 116 cGy/min D0 134.3, n 1.57). Expression in NIH/3T3 of transfected oncogenes v-abl, v-fms, v-fos, or H-ras increased radioresistance at low dose rate (D0 208.6, n 1.61; D0 206.6, n 1.51; D0 167.5, n 1.85; and D0 206.8, n 1.08, respectively). Thus expression of each of several oncogenes induces resistance to gamma irradiation at 5 cGy/min in hematopoietic and fibroblast cell lines. These data may help explain the clinical recurrence of oncogene-expressing leukemia and lymphoma cells after marrow stem cell ablative doses of low-dose-rate total-body irradiation.
 ...
PMID:Expression of transfected recombinant oncogenes increases radiation resistance of clonal hematopoietic and fibroblast cell lines selectively at clinical low dose rate. 232 Jul 25

NK cells preferentially kill normal embryonic fibroblasts. Because embryonic cells are growth factor responsive and maintain high proliferative rates, we examined the requirement for growth factor-initiated proliferation for NK susceptibility. Murine embryonic fibroblasts made quiescent in defined medium lacking growth factors were relatively resistant to NK cytolysis. However, reinitiation of proliferation with basic fibroblast growth factor (bFGF) or epidermal growth factor enhanced lysis in a dose-dependent fashion. TGF-beta, which blocked cell division, did not enhance cytotoxicity. Additionally, growth inhibition by prolonged incubation at confluence suppressed lysis. The enhanced NK cytotoxicity of bFGF-stimulated fibroblasts was caused by a post-binding event because no difference in cold target inhibition could be demonstrated with bFGF-treated cells. NK cytotoxicity has largely been attributed to the action of cytotoxins released from cytoplasmic granules. In a 51Cr release assay, bFGF-treated fibroblasts were insensitive to NK granules isolated from the RNK large granular lymphocyte leukemia. However, these same cells exhibited marked sensitivity to lysis in an 18-h adhesion assay normally utilized to detect TNF-alpha. With the use of this assay, a dose-dependent increase in sensitivity of bFGF-treated fibroblasts was observed, whereas quiescent fibroblasts were resistant to the action of isolated NK granules. Granule cytotoxicity was not caused by cytolysin/perforin because inactivation of granule hemolytic activity with CaCl2 did not affect fibroblast killing, and bFGF-treated cells were insensitive to purified cytolysin/perforin. This suggested that another granule associated cytotoxin was responsible for enhanced NK sensitivity of actively proliferating fibroblasts.
 ...
PMID:Growth factor-initiated proliferation of mouse embryonic fibroblasts induces cytotoxicity by natural killer cells and by a non-cytolysin cytotoxin in natural killer granules. 238 May 58


1 2 3 4 5 6 7 8 9 10 Next >>