Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 high-affinity IgE receptor (Fc epsilon RI), which is expressed on the surface of mast cells and basophils, has a central role in immediate allergic responses. In the rat basophilic leukaemia cell line RBL-2H3, which is a model system for the analysis of Fc epsilon RI-mediated signal transduction, surface engagement of Fc epsilon RI induces histamine release and the tyrosine phosphorylation of several distinct proteins. Although the alpha, beta, and gamma subunits of Fc epsilon RI lack intrinsic tyrosine protein kinase (TPK) activity, a kinase that copurifies with Fc epsilon RI phosphorylates the beta and gamma subunits of the receptor on tyrosine residues. We report here that in RBL-2H3 cells, p56lyn and pp60c-src are activated after Fc epsilon RI crosslinking, and p56lyn coimmunoprecipitates with Fc epsilon RI. In the mouse mast-cell line PT-18, another cell type used to study FC epsilon RI-mediated signalling, tyrosine phosphorylation of proteins is also an immediate consequence of receptor crosslinking. Notably, the only detectable src protein-related TPK in PT-18 cells is p62c-yes, and it is this TPK that is activated on Fc epsilon RI engagement and coimmunoprecipitates with the receptor. Therefore, it seems that different src protein-related TPKs can associate with the same receptor and become activated after receptor engagement.
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PMID:Engagement of the high-affinity IgE receptor activates src protein-related tyrosine kinases. 137 May 75

We have previously described differentiation associated tyrosine protein kinase activity in WEHI-3B monomyelocytic leukemia cells and have presented evidence which suggests that this activity may not be involved in the initiation of the differentiation process, but more likely has a functional role in the mature myeloid cell. The present study was undertaken in an attempt to identify the protein(s) responsible for the tyrosine protein kinase activity and to seek a potential role for this activity in the mature cell. We and others have detected the p92c-fes tyrosine protein kinase in WEHI-3B cells. This protein has been implicated in myeloid differentiation, as well as in the transduction of signals in response to granulocyte macrophage colony stimulating factor (GM-CSF). Thus, it was of interest to determine whether tyrosine phosphorylation may be involved in the response of WEHI-3B cells to GM-CSF. Treatment of differentiated WEHI-3B D+ cells with GM-CSF was found to result in the tyrosine phosphorylation of a number of endogenous cellular proteins in a concentration-dependent, rapid and transient manner. In contrast, the cytokine did not elicit such a response in undifferentiated cells, despite the fact that undifferentiated cells have been reported to possess GM-CSF receptors. These findings are consistent with the concept that the effects of GM-CSF on differentiated myeloid cells are mediated through tyrosine phosphorylation, that only differentiated cells are competent to accomplish this event, and that this response constitutes at least one functional role for the myeloid differentiation associated tyrosine protein kinase activity.
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PMID:Differentiation stage specificity of tyrosine phosphorylation in response to granulocyte macrophage colony stimulating factor (GM-CSF). 155 4

p56lck, a tyrosine protein kinase of the src family, is overexpressed in two murine thymoma cell lines, LSTRA and Thy19, as a result of the integration of Moloney murine leukemia virus sequences upstream of the lck gene. The majority of the p56lck in these cell lines is translated from a hybrid mRNA comprised of the 5' untranslated region of the murine leukemia virus env mRNA and lck coding sequences. The retroviral promoter giving rise to this transcript has been molecularly cloned. To examine whether overexpression of unmutated p56lck might induce cellular transformation, we constructed a plasmid in which the murine leukemia virus promoter from LSTRA cells directed the expression of p56lck. This construct gave rise to foci when transfected into rat 208F fibroblasts. Cells from many of the foci also grew in soft agar. Tryptic peptide mapping showed that the p56lck in the transformed cells was phosphorylated at Tyr-394, the autophosphorylation site, but not detectably at Tyr-505, an inhibitory site. Because an antiserum made to the carboxy terminus of p56lck could not immunoprecipitate p56lck from these transformed cells, the possibility arose that the proteins expressed in the transformed fibroblasts contained mutations that altered the carboxy terminus of the protein. cDNAs derived from the 3' ends of the lck mRNAs in two of the foci were cloned, and both were found to be derived from an lck gene that was truncated upstream of the codon for Tyr-505 and fused to random sequences derived from other parts of the construct used for transfection. lck therefore resembles several other src family members in that it can be rendered oncogenic by replacement of the region encoding the inhibitory, carboxy-terminal phosphorylation site by random amino acid sequences.
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PMID:Generation and characterization of transforming variants of the lck tyrosine protein kinase. 159 48

Abelson murine leukemia virus is an acutely transforming replication-defective virus which encodes a transforming protein with tyrosine-specific protein kinase activity. A variety of benzopyranone and benzothiopyranone derivatives have been identified which selectively inhibit the v-abl tyrosine protein kinase with 50% inhibitory concentrations ranging from 1 to 30 microM. The most active derivative inhibited v-abl with a Ki value of 0.9 microM. Active derivatives showed selectivity for the v-abl tyrosine protein kinase relative to the epidermal growth factor receptor tyrosine protein kinase (50% inhibitory concentration greater than 100 microM). Protein kinase C and protein kinase A, two members of the serine/threonine protein kinase family, were not inhibited by benzopyranones or benzothiopyranones (50% inhibitory concentration greater than 100 microM). Kinetically, a representative derivative (compound 2) showed competitivity with respect to ATP and noncompetitive behavior with respect to the exogenous peptide substrate. Autophosphorylation of p120v-abl and recombinant p70v-abl tyrosine protein kinases were also inhibited by benzopyranones and benzothiopyranones in vitro. When tested in Abelson murine leukemia virus-transformed BALB/c cell, active benzopyranone and benzothiopyranone derivatives inhibited tyrosine phosphorylation of cellular proteins by the v-abl tyrosine protein kinase.
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PMID:Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. 164 41

The lck gene encodes a lymphocyte-specific tyrosine protein kinase, p56lck, the expression of which is almost exclusive in T-cells. The expression of lck in human T-cell leukemia virus type I (HTLV-I)-transformed T-cell lines is closely associated with interleukin-2 (IL-2) dependence for their growth. That is, IL-2-dependent HTLV-I-transformed cell lines contain the lck message abundantly as HTLV-I-negative T-cell lines, whereas IL-2-independent HTLV-I-transformed cell lines express either no or little lck mRNA, although they are derived from T-cells. The lck gene contains 2 distinct promoters which direct 2 types of lck transcript with different 5' untranslated regions. In this study, we show that HTLV-I-transformed IL-2-dependent T-cell lines contain the upstream promoter-initiated lck transcript exclusively, in contrast to HTLV-I-negative transformed T-cell lines which express the down-stream promoter- as well as the upstream promoter-initiated lck transcript. In addition, lck mRNA disappears transiently in IL-2-dependent HTLV-I-transformed T-cell lines after stimulation for T-cell activation, which is also observed in peripheral blood T lymphocytes. These results indicate that the disappearance of lck mRNA in HTLV-I-transformed, IL-2-independent cell lines is caused by a mechanism which down-regulates the upstream promoter-initiated lck transcript and this IL-2-independent state may represent a further "activated" condition of the IL-2-dependent state by the stimulation which mediates T-cell activation.
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PMID:Differential expression of two lck transcripts directed from the distinct promoters in HTLV-I+ and HTLV-I- T-cells. 171 60

Tyrosine protein kinase activity was examined during the induction of granulocytic differentiation of WEHI-3B murine monomyelocytic leukemia cells by retinoic acid and aclacinomycin A. Tyrosine kinase activity was found to increase throughout the period of induced maturation. The specificity of this increase in enzymatic activity for the differentiated state was demonstrated by the findings that (a) it was independent of the inducer used, and (b) the treatment of a differentiation-resistant subline of this murine leukemia with an inducer did not produce a significant elevation of tyrosine kinase activity. To determine whether tyrosine protein kinase activity was involved in the differentiation process itself or whether it was a product of the mature state, a series of experimental approaches was employed. Kinetic analyses showed that tyrosine protein kinase activity continued to increase beyond the peak in the level of differentiation. In addition, the total cellular protein phosphotyrosine content, measured by immunoblotting and flow cytometric analysis with anti-phosphotyrosine antibodies, did not increase in accord with the elevation of tyrosine kinase activity. Increases in protein phosphotyrosine content, which were dependent upon the length of exposure to the inducing agent, were observed when cultured cells were treated with the phosphotyrosine phosphatase inhibitor, sodium orthovanadate. Thus, the effect of the increasing tyrosine kinase activity in maturing cells appeared to be negated by competing protein phosphotyrosine phosphatase activity. Finally, the inhibitors of tyrosine kinase activity, genistein and PKI-23, did not interfere with the induction of differentiation by retinoic acid. These findings support the concept that myeloid differentiation associated tyrosine protein kinase activity may not be involved in the initiation of the differentiation process itself. This conclusion deviates from previous assumptions, based on earlier work in this laboratory as well as in that of others, that the differentiation associated kinase activity has an essential role in the initiation of the maturation process. An attractive alternative speculation is that this activity may have a functional role in the mature myeloid cell.
Leukemia 1991 Oct
PMID:Myeloid differentiation associated tyrosine protein kinase activity in WEHI-3B murine monomyelocytic leukemia cells. 172 Apr 91

Transformation of lymphoid and fibroblastic cells by Abelson murine leukemia virus (A-MuLV) is mediated by the viral tyrosine protein kinase. We do not yet know the important target proteins in the cell, the host proteins that modulate the kinase activity, or the host proteins involved in the signal-transduction pathway ultimately leading to altered patterns of cell growth. As a first step toward identifying these host proteins, we have isolated and characterized several flat revertant cell lines from transformed lines carrying v-abl. Clonal transformed cell lines used as parental strains were prepared by infecting Rat-2 fibroblasts with A-MuLV, using M-MuLV as helper. A rhodamine dye screening procedure was used to obtain three clones of morphologically flat revertant cells. Each of the three lines was non-refractile and contact inhibited. All the lines retained a transformation-competent copy of A-MuLV; all released high titers of virus capable of inducing foci on previously uninfected Rat-2 cells. Analyses of the revertant lines suggest that diverse mechanisms can lead to loss of transformed morphology.
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PMID:Isolation and characterization of flat revertant cell lines from A-MuLV-transformed fibroblasts. 215 87

The Drosophila melanogaster abl and the murine v-abl genes encode tyrosine protein kinases (TPKs) whose amino acid sequences are highly conserved. To assess functional conservation between the two gene products, we constructed Drosophila abl/v-abl-chimeric Abelson murine leukemia viruses. In these chimeric Abelson murine leukemia viruses, the TPK and carboxy-terminal regions of v-abl were replaced with the corresponding regions of D. melanogaster abl. The chimeric Abelson murine leukemia viruses were able to mediate morphological and oncogenic transformation of NIH 3T3 cells and were able to abrogate the interleukin-3 dependence of a lymphoid cell line. We also found that a virus that contained both TPK and carboxy-terminal Drosophila abl regions had no in vitro transforming activity for primary bone marrow cells and lacked the ability to induce tumors in susceptible mice. A virus that replaced only a portion of the v-abl TPK region with that of Drosophila abl had low activity in in vitro bone marrow transformation and tumorigenesis assays. These results indicate that the transforming functions of abl TPKs are only partially conserved through evolution. These results also imply that the TPK region of v-abl is a major determinant of its efficient lymphoid cell-transforming activity.
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PMID:Conservation of function of Drosophila melanogaster abl and murine v-abl proteins in transformation of mammalian cells. 215 82

We have assessed whether tyrosine protein kinase (TPK) is involved in B cell differentiation. In vitro phosphorylation of an endogenous substrate in B cell leukemias showed that leukemic B cells at different stages of differentiation had specific endogenous substrates in tyrosine phosphorylation as well as distinct TPK activity. To clarify the relationship between TPK and the process of B cell differentiation, we studied protein tyrosine phosphorylation in two kinds of leukemic B cells, which showed distinct responses to TPA (12-O-tetradecanoylphorbol-13-acetate) in B cell differentiation. TPA-treated leukemic B cells from patients with B cell chronic lymphocytic leukemia (B-CLL) differentiated into cytoplasmic immunoglobulin (clg)+ plasmacytoid cells, while TPA-treated leukemic B cells from patients with hairy cell leukemia (HCL) did not differentiate into clg+ cells, but showed a peculiar morphological change, spreading. Untreated B-CLL cells and HCL cells showed similar TPK activities and tyrosine protein phosphorylation. When treated with TPA, enhanced phosphorylation was seen in B-CLL cells, while a clear reduction in phosphorylation was found in HCL cells. However, using 4-hydroxycinnamide derivatives which reduce TPK activity, we found that only the reduction of TPK activity did not lead HCL cells to spreading. These data suggest that protein tyrosine phosphorylation and/or dephosphorylation might be involved in B cell differentiation, but only the change of TPK activity in HCL cells is not sufficient to induce effects.
Leukemia 1990 Oct
PMID:Association of protein tyrosine phosphorylation with B cell differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). 221 73

In chronic granulocytic leukemia (CGL) the Philadelphia translocation results in the production of a novel 210 kDa bcr-abl fusion protein which shows increased tyrosine protein kinase activity in comparison with its normal 145 kDa c-abl counterpart. Using an immunoblotting method and antiphosphotyrosine antibody, we have identified the tyrosine protein kinase substrates present in intact cells from two Philadelphia-positive CGL derived cell lines (K562 and BV173) and compared these with the substrates present in a Philadelphia-negative myeloid cell line (HL60). We have demonstrated an increased number of substrates, particularly of low (less than 110 kDa) molecular weight in the K562 or BV173 cells compared with the HL60 cells. There is virtual identity of the substrates present in the two CGL-derived lines. This work supports the hypothesis that the functional changes present in the bcr-abl 210 kDa protein of CGL results in altered tyrosine phosphorylation of intracellular proteins and that this is of importance in the pathogenesis of CGL.
Leukemia 1987 Jun
PMID:Tyrosine protein kinase substrates in Philadelphia-positive human chronic granulocytic leukemia derived cell lines (K562 and BV173): detection by using an immunoblotting technique. 244 34


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