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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital mesoblastic nephroma (CMN) is a rare renal tumor of early infancy with a favorable outcome after complete surgical removal. CMN consists of a heterogeneous group of spindle cell tumors subdivided into "classical", "cellular or atypical" and "mixed" forms based on histologic features. We describe a new case of cellular CMN diagnosed by antenatal ultrasonography with complete remission five years after nephrectomy. Cytogenetic study evidenced a trisomy 11, and real time RT-PCR, but not conventional karyotype, allowed for the detection of the Tel-ETV6/TrkC-NTRK3 fusion transcript as a consequence of a cryptic t(12-15)(p13;q25). As in congenital fibrosarcoma (CFS), two Tel-ETV6/ TrkC-NTRK3 fusion transcripts different by a 42 bp insert in the TrkC kinase domain were expressed. Our observations outline the close links between cellular CMN and CFS. Both tumors have the clinical presentation and histologic features as well as identical cytogenetic and molecular markers in common. Therefore, they are likely to represent the same neoplasm, but occurring at different locations.
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PMID:Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma. 1265 May 16

The TEL/PDGFbetaR oncogenic fusion protein is the product of the t(5;12)(q33; p13) translocation recurrently found in patients with chronic myelomonocytic leukemia (CMML). To investigate the coupling of molecular signaling events activated by TEL/PDGFbetaR to functional responses, we expressed TEL/PDGFbetaR in interleukin 3 (IL-3)-dependent BaF/3 cells using the tetracycline-regulated expression system. Induction of TEL/PDGFbetaR expression led to increased cell survival following IL-3 withdrawal and constitutive activation of protein kinase B (PKB), signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinases 1/2 (ERK1/2), Jun N-terminal kinases 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (MAPK) pathways. However, inducible expression of TEL/PDGFbetaR failed to generate factor-independent cells, whereas constitutive expression of TEL/PDGFbetaR did, albeit at low frequency, suggesting the duration of TEL/PDGFbetaR expression is important for transformation. Surprisingly, in cells induced to express TEL/PDGFbetaR, IL-3-dependent growth was dramatically reduced as a result of increased apoptosis of cells receiving combined IL-3 and TEL/PDGFbetaR signals. We demonstrate that TEL/PDGFbetaR expression augmented IL-3-induced activation of PKB, STAT5, ERK1/2, p38, and JNK1/2. Inhibition of neither phosphoinositide-3 kinases nor p38 MAPKs reduced the inhibition of IL-3-driven proliferation observed when TEL/PDGFbetaR was expressed. However, inhibition of MEKs or JNKs partially reversed the combined inhibitory effects of TEL/PDGFbetaR and IL-3 on proliferation and survival. These results suggest that the combination of TEL/PDGFbetaR and IL-3-induced signals activate apoptosis through ERK and JNK MAPK-dependent pathways. Given that in vivo hematopoietic cells are in contact with a variety of cytokines, our results have important implications for cellular responses in the pathogenesis of CMML.
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PMID:The coupling of TEL/PDGFbetaR to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases. 1271 13

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

Over the past 6 years, molecular genetic studies have significantly advanced our understanding of pediatric renal neoplasms. The cellular variant of congenital mesoblastic nephroma (but not the classic variant) has been shown to bear the same t(12;15)(p13;q25) and ETV6-NTRK3 gene fusion as infantile fibrosarcoma, a tumor with which it shares morphologic and clinical features. Rhabdoid tumor of the kidney is characterized by deletion of the hSNF5/INI1 gene, which links it to other rhabdoid tumors of infancy that arise in the soft tissue and brain. Primary renal synovial sarcomas and renal primitive neuroectodermal tumors have become accepted entities, and likely comprise a subset of what had previously been termed "adult Wilms tumor." Renal carcinomas associated with Xp11.2 translocations that result in fusions involving the TFE3 transcription factor gene have been delineated, including a distinctive neoplasm that shares the identical gene fusion as alveolar soft part sarcoma. Most recently, a distinctive type of renal neoplasm with a t(6;11)(p21;q12) has been described, and the cloning of the resulting gene fusion links it to the Xp11 translocation carcinomas. Together, these last two translocation-associated tumors represent a significant proportion of pediatric renal cell carcinomas. This review highlights each of these recent advances.
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PMID:Recent advances in pediatric renal neoplasia. 1297 47

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

Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2APBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy.
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PMID:FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. 1450 97

The authors describe a patient with a large retroperitoneal infantile fibrosarcoma that responded well to preoperative chemotherapy, which subsequently facilitated the complete surgical resection of the mass. The patient had an unusual site of metastasis presumed to be to a regional lymph node. The histology on initial core biopsies was not classic but showed a round cell, myxoid pattern. The presence of the t(12;15)(p13;q25) and the fusion transcript ETV6-NTRK3 by RTPCR facilitated the diagnosis.
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PMID:Retroperitoneal infantile fibrosarcoma: clinical, molecular, and therapeutic aspects of an unusual tumor. 1457 34

Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN.IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation.
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PMID:A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation. 1466 42

Activating mutations of the FLT3 receptor tyrosine kinase are common in acute myelogenous leukemia (AML) but are rare in adult acute lymphoblastic leukemia (ALL). We have recently shown that FLT3 is highly expressed and often mutated in ALLs with rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Because hyperdiploid ALL samples also show high-level expression of FLT3, we searched for the presence of FLT3 mutations in leukemic blasts from 71 patients with ALL. The data show that approximately 25% (6 of 25) of hyperdiploid ALL samples possess FLT3 mutations, whereas only 1 of 29 TEL/AML1-rearranged samples harbored mutations (P =.04, Fisher exact test). Three mutations are novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. Finally, 3 samples from patients whose disease would relapse harbored FLT3 mutations. These data suggest that patients with hyperdiploid or relapsed ALL might be considered candidates for therapy with newly described small-molecule FLT3 inhibitors.
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PMID:FLT3 mutations in childhood acute lymphoblastic leukemia. 1467 Sep 24

Imatinib mesylate treatment is highly effective in chronic myeloid leukaemia and recent data have suggested that imatinib mesylate is also effective in the treatment of idiopathic hypereosinophilic syndrome (HES). Six patients with HES were treated daily with 100 mg imatinib mesylate. Five patients had normal karyotype and one showed trisomy 8. RT-PCR was negative for ETV6-PDGFRB and BCR-ABL fusion mRNAs. All patients rapidly achieved complete haematological remission. One patient remained in remission for more than 6 weeks after discontinuing treatment. No significant side effect was noted. Imatinib mesylate should be considered in the first-line therapy of idiopathic HES.
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PMID:Effective treatment of hypereosinophilic syndrome with imatinib mesylate. 1467 12


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