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: KEGG:D01078 (TEL)
781 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligomerization of the nonreceptor tyrosine kinase c-Abl can activate its transforming potential. Domains mediating oligomerization within the BCR-ABL and TEL-ABL oncoproteins are required for transforming activity, and fusion of inducible dimerization domains to c-Abl can generate chimeric proteins with dimerization-dependent transforming activity. We have found that c-Abl oligomerizes at high levels of expression in COS cells. This interaction is dependent on kinase activity and an intact NH(2)-terminal region of c-Abl. A binding partner of c-Abl, Abl-interactor-1 (Abi-1), similarly oligomerizes in COS cells. An oligomeric form of Abi-1 interacts with Abl both in vitro and in mammalian cells. These results suggest the possibility that oligomerization of Abl kinases, perhaps involving regulation by their interaction partners, may play a role in modulation of kinase activity in both normal and oncogenic processes.
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PMID:Homo- and hetero-oligomerization of the c-Abl kinase and Abelson-interactor-1. 1259 40

Translocations involving the abl locus on chromosome 9 fuses the tyrosine kinase c-ABL to proteins harboring oligomerization interfaces such as BCR or TEL, enabling these ABL-fusion proteins (X-ABL) to transform cells and to induce leukemia. The ABL kinase activity is blocked by the ABL kinase inhibitor STI571 which abrogates transformation by X-ABL. To investigate the role of oligomerization for the transformation potential of X-ABL and for the sensitivity to STI571, we constructed ABL chimeras with oligomerization interfaces of proteins involved in leukemia-associated translocations such as BCR, TEL, PML, and PLZF. We assessed the capacity of these chimeras to form high molecular weight (HMW) complexes as compared with p185(BCR-ABL). There was a direct relationship between the size of HMW complexes formed by these chimeras and their capacity to induce factor independence in Ba/F3 cells, whereas there was an inverse relationship between the size of the HMW complexes and the sensitivity to STI571. The targeting of the oligomerization interface of p185(BCR-ABL) by a peptide representing the coiled coil region of BCR reduced its potential to transform fibroblasts and increased sensitivity to STI571. Our results indicate that targeting of the oligomerization interfaces of the X-ABL enhances the effects of STI571 in the treatment of leukemia caused by X-ABL.
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PMID:Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571. 1282 85

The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in expression of the RUNX1-CBF2T1 [AML1-ETO (AE)] fusion oncogene. AML/ETO may contribute to leukemogenesis by interacting with nuclear corepressor complexes that include histone deacetylases, which mediate the repression of target genes. However, expression of AE is not sufficient to transform primary hematopoietic cells or cause disease in animals, suggesting that additional mutations are required. Activating mutations in receptor tyrosine kinases (RTK) are present in at least 30% of patients with AML. To test the hypothesis that activating RTK mutations cooperate with AE to cause leukemia, we transplanted retrovirally transduced murine bone marrow coexpressing TEL-PDGFRB and AE into lethally irradiated syngeneic mice. These mice (19/19, 100%) developed AML resembling M2-AML that was transplantable in secondary recipients. In contrast, control mice coexpressing with TEL-PDGFRB and a DNA-binding-mutant of AE developed a nontransplantable myeloproliferative disease identical to that induced by TEL-PDGFRB alone. We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate. We found that although imatinib prolonged the survival of treated mice, histone deacetylase inhibitors provided no additional survival benefit. These data demonstrate that an activated RTK can cooperate with AE to cause AML in mice, and that this system can be used to evaluate novel therapeutic strategies.
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PMID:An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. 1288 86

TEL is a frequent target of chromosomal translocations in human cancer and an alleged tumor suppressor gene. TEL encodes two isoforms: a major TEL-M1 isoform as well as TEL-M43, which lacks the first 42 amino acid residues of TEL-M1. Both isoforms are potent transcriptional repressors that can inhibit RAS-induced transformation. Here we show that the v-SRC protein-tyrosine kinase relieves the repressive activity of TEL-M1, an activity that is associated with the v-SRC-induced delocalization of TEL-M1 from the nucleus to the cytoplasm. TEL-M1 delocalization requires the kinase activity of v-SRC and is not induced by oncogenic RAS or AKT. Cytoplasmic delocalization of TEL-M1 in response to v-SRC critically depends upon its unique amino-terminal domain (SRCD domain) because (i). v-SRC did not inhibit the repressive properties of TEL-M43, nor affected TEL-M43 nuclear localization; (ii). fusion of the first 52 amino acid residues of TEL-M1 to FLI-1, an ETS protein insensitive to v-SRC-induced delocalization, is sufficient to confer v-SRC-induced delocalization to this TEL/FLI-1 chimeric protein. The v-SRC-induced nucleo-cytoplasmic delocalization of TEL-M1 does not involve phosphorylation of the SRCD and does not require TEL self-association and repressive domains. Finally, enforced expression of the v-SRC-insensitive TEL-M43, but not of TEL-M1, inhibits v-SRC-induced transformation of NIH3T3 fibroblasts. These results identify a regulatory domain in TEL that specifically impinges on the subcellular localization of its major TEL-M1 isoform. They, furthermore, indicate that inhibition of TEL-M1 nuclear function is required for v-SRC to induce cellular transformation.
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PMID:v-SRC specifically regulates the nucleo-cytoplasmic delocalization of the major isoform of TEL (ETV6). 1289 22

The Met receptor tyrosine kinase has been shown to be overexpressed or mutated in a variety of solid tumors and has, therefore, been identified as a good candidate for molecularly targeted therapy. Activation of the Met tyrosine kinase by the TPR gene was originally described in vitro through carcinogen-induced rearrangement. The TPR-MET fusion protein contains constitutively elevated Met tyrosine kinase activity and constitutes an ideal model to study the transforming activity of the Met kinase. We found, when introduced into an interleukin 3-dependent cell line, TPR-MET induces factor independence and constitutive tyrosine phosphorylation of several cellular proteins. One major tyrosine phosphorylated protein was identified as the TPR-MET oncoprotein itself. Inhibition of the Met kinase activity by the novel small molecule drug SU11274 [(3Z)-N-(3-chlorophenyl)-3-([3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl]methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] led to time- and dose-dependent reduced cell growth. The inhibitor did not affect other tyrosine kinase oncoproteins, including BCR-ABL, TEL-JAK2, TEL-PDGFbetaR, or TEL-ABL. The Met inhibitor induced G(1) cell cycle arrest and apoptosis with increased Annexin V staining and caspase 3 activity. The autophosphorylation of the Met kinase was reduced on sites that have been shown previously to be important for activation of pathways involved in cell growth and survival, especially the phosphatidylinositol-3'-kinase and the Ras pathway. In particular, we found that the inhibitor blocked phosphorylation of AKT, GSK-3beta, and the pro-apoptotic transcription factor FKHR. The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase.
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PMID:A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. 1450 Mar 82

The TEL/ARG oncogene associated with acute myeloid leukemia is formed by the t(1;12)(q25;p13) reciprocal translocation, which fuses part of the TEL gene to the tyrosine kinase, c-ARG. In an effort to determine the biological effects and investigate signaling of the TEL/ARG fusion protein, multiple sublines of Ba/F3 cells were generated in which a TEL/ARG complementary DNA was expressed under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, rapidly induced expression of the TEL/ARG protein. TEL/ARG was heavily phosphorylated on tyrosine residues and was also found to rapidly induce tyrosine phosphorylation of multiple cellular proteins, including rasGAP, CBL, STAT5, PI3K, SHP2, Dok, and SHC. The Ba/F3-tet-TEL/ARG cells remained interleukin (IL)-3 dependent without doxycycline but with doxycycline displayed a marked reduction in cell death in the absence of IL-3. TEL/ ARG cells also displayed an enhanced proliferative response to IL-3 and to insulin-like growth factor 1. At least in Ba/F3 cells, although the growth rate was much lower compared to that with IL-3, TEL/ARG appeared to induce some cell proliferation as an immediate consequence. Nonetheless, the hyperresponsiveness to growth factors reported here is more likely to contribute to the pathogenesis of leukemia.
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PMID:The TEL/ARG leukemia oncogene promotes viability and hyperresponsiveness to hematopoietic growth factors. 1500 41

The TEL-PDGFRB fusion oncogene is associated with chronic myelomonocytic leukemia (CMML) and results in the expression of a constitutively active tyrosine kinase. SU11657 is a multitargeted selective inhibitor of class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors KIT and FLT3. SU11657 inhibited TEL/PDGFbetaR kinase activity at nanomolar concentrations and inhibited TELPDGFRB-mediated factor-independent growth in myeloblastic 32D cells. Daily oral administration of SU11657 at 40 mg/kg suppressed myeloproliferation and significantly prolonged survival in TELPDGFRB mice treated prior to disease development, as well as in those with large tumor burdens. Our findings suggest that SU11657 or similar agents may have therapeutic potential in humans with hematologic malignancies expressing PDGFR fusion oncogenes.
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PMID:Complete remission of TEL-PDGFRB-induced myeloproliferative disease in mice by receptor tyrosine kinase inhibitor SU11657. 1504 54

TEL-platelet-derived growth factor-beta receptor (TEL-PDGFbetaR) is expressed in chronic myelomonocytic leukemias associated with t(5;12)(q33;p13), and the fusion tyrosine kinase retains a conserved WW-like domain in the PDGFbetaR autoinhibitory juxtamembrane region. Here we report that mutation of the 2 conserved tryptophan residues of the WW-like domain has opposing effects on TELPDGFbetaR kinase activation. Alanine substitution of W593, essential for protein-protein interaction in the context of other WW domains, impaired TEL-PDGFbetaR-mediated transformation of hematopoietic cells due to inhibition of TEL-PDGFbetaR kinase activity. In contrast, alanine substitution of W566, essential for structural integrity of WW domain in other contexts, had no effect on TEL-PDGFbetaR activation and oncogenic activity. Surprisingly, however, the W566A mutation suppressed the W593A phenotype. Double mutant W566A/W593A was indistinguishable from the wild-type fusion protein with regard to kinase activity, ability to confer factor-independent growth to Ba/F3 cells, or ability to induce a myeloproliferative disease in mice. Additional mutational analysis identified other substitutions within the WW-like domain in addition to W566A that could also suppress the W593A phenotype, including mutations predicted to diminish the autoinhibitory function of the juxtamembrane region. Therefore, the WW-like domain in the context of TELPDGFbetaR may have both positive and negative regulatory roles in kinase activation.
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PMID:Positive and negative regulatory roles of the WW-like domain in TEL-PDGFbetaR transformation. 1505 45

Myeloid leukaemias are frequently associated with translocations and mutations of tyrosine kinase genes. The products of these oncogenes, including BCR-ABL, TEL-PDGFR, Flt3 and c-Kit, have elevated tyrosine kinase activity and transform haematopoietic cells, mainly by augmentation of proliferation and enhanced viability. Activated ABL kinases are associated with chronic myeloid leukaemia. Mutations in platelet-derived growth factor receptor beta are associated with chronic myelomonocytic leukaemia. Flt3 or c-Kit cooperate with other types of oncogenes to create fully transformed acute leukaemias. Elevated activity of these tyrosine kinases is crucial for transformation, thus making the kinase domain an ideal target for therapeutic intervention. Tyrosine kinase inhibitors for various kinases are currently being evaluated in clinical trials and are potentially useful therapeutic agents in myeloid leukaemias. Here, the authors review the signalling activities, mechanism of transformation and therapeutic targeting of several tyrosine kinase oncogenes important in myeloid leukaemias.
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PMID:Targeting mutated tyrosine kinases in the therapy of myeloid leukaemias. 1516 29

Small molecule inhibitors, such as imatinib, are effective therapies for tyrosine kinase fusions BCR-ABL-TEL-PDGFbetaR-mediated human leukemias, but resistance may develop. The unique fusion junctions of these molecules are attractive candidates for molecularly targeted therapeutic intervention using RNA interference (RNAi), which is mediated by small interfering RNA (siRNA). We developed a retroviral system for stable expression of siRNA directed to the unique fusion junction sequence of TEL-PDGFbetaR in transformed hematopoietic cells. Stable expression of the siRNA resulted in approximately 90% inhibition of TEL-PDGFbetaR expression and its downstream effectors, including PI3K and mammalian target of rapamycin (mTOR). Expression of TEL-PDGFbetaR-specific siRNA (TPsiRNA) significantly attenuated the proliferation of TEL-PDGFbetaR-transformed Ba/F3 cells or disease latency and penetrance in mice induced by intravenous injection of these Ba/F3 cells. Although a 90% reduction in TEL-PDGFbetaR expression was insufficient to induce cell death, stable siRNA expression sensitized transformed cells to the PDGFbetaR inhibitor imatinib or to the mTOR inhibitor rapamycin. TPsiRNA also inhibited an imatinib-resistant TEL-PDGFbetaR mutant, and the inhibition was enhanced by siRNA in combination with PKC412, another PDGFbetaR inhibitor. Although siRNA delivery in vivo is a challenging problem, stable expression of siRNA, which targets oncogenic fusion genes, may potentiate the effects of conventional therapy for hematologic malignancies.
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PMID:Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin. 1519 13


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