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)

The ubiquitin system has been recently implicated in various aspects of transcriptional regulation, including proteasome-dependent degradation of transcriptional activators. In yeast, the activator Met4 is inhibited by the SCF(Met30) ubiquitin ligase, which recognizes and oligo-ubiquitylates Met4. Here, we demonstrate that in minimal media, Met4 is ubiquitylated and rapidly degraded in response to methionine excess, whereas in rich media, Met4 is oligo-ubiquitylated but remains stable. In the latter growth condition, oligo-ubiquitylated Met4 is not recruited to MET gene promoters, but is recruited to the SAM genes, which are required for production of S-adenosylmethionine, an unstable metabolite that is not present in rich medium. Thus, ubiquitylation not only regulates Met4 by distinct degradation-dependent and -independent mechanisms, but also controls differential recruitment of a single transcription factor to distinct promoters, thereby diversifying transcriptional activator specificity.
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PMID:Dual regulation of the met4 transcription factor by ubiquitin-dependent degradation and inhibition of promoter recruitment. 1215 Sep 8

Recovery from radiation-induced (RI) myelosuppression depends on hematopoietic stem and progenitor cell survival and the active proliferation/differentiation process, which requires early cytokine support. Single cytokine or late-acting growth factor therapy has proved to be inefficient in ensuring reconstitution after severe RI damage. This work was aimed at evaluating the in vivo survival effect of combinations of early-acting cytokines whose antiapoptotic activity has been demonstrated in vitro: stem cell factor (SCF [S]), FMS-like tyrosine kinase 3 ligand (FLT-3 ligand [F]), thrombopoietin (TPO [T]), interleukin-3 (IL-3 [3]), and stromal derived factor-1 (SDF-1). B6D2F1 mice underwent total body irradiation at 8 Gy cesium Cs 137 gamma radiation (ie, lethal dose 90% at 30 days) and were treated soon after irradiation, at 2 hours and at 24 hours, with recombinant murine cytokines, each given intraperitoneally at 50 microg/kg per injection. All treatments induced 30-day survival rates significantly higher than control (survival rate, 8.3%). 4F (SFT3) and 5F (4F + SDF-1) were the most efficient combinations (81.2% and 87.5%, respectively), which was better than 3F (SFT, 50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better than 4F given at 10 microg/kg per injection (4F10, 45.8%) or as a 50 microg/kg single injection at 2 hours (4Fs, 62.5%). Despite delayed death occurring mainly from day 150 on and possible long-term hematopoiesis impairment, half the 30-day protective effects of 4F and 5F were preserved at 300 days. Our results show that short- and long-term survival after irradiation depends on appropriate multiple cytokine combinations and at optimal concentrations. The proposal is made that an emergency cytokine regimen could be applied to nuclear accident victims as part of longer cytokine treatment, cell therapy, or both.
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PMID:Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival. 1246 35

The ability of acute myeloid leukaemia (AML) cells to acquire dendritic cell (DC)-like characteristics in vitro with a rapid culture method based either on the phorbol ester PMA or calcium ionophores has been studied in comparison to conventional AML-DC cultures with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML patients, antigen-presenting cells (APC) could be generated from leukaemic cells in 2 days by incubation with PMA or calcium ionophore (A23187 or ionomycin) in the presence as well as in the absence of IL-4. In 30 out of 36 patients APC could be generated after 2 weeks of culture in cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores immunophenotypically and functionally were at a more mature stage than those cultured in cytokine-enriched medium. The most mature APC were generated by calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards AML blast cells in vitro was observed in 2 cases tested. The persistence of cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The generation of AML-APC was possible from freshly isolated as well as cryopreserved material. Our data show that generation of sufficient AML-APC by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately 70% of AML specimens, offering a time-saving and cost-effective approach in preparing anti-leukaemia vaccines.
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PMID:Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. 1253 36

Melanoma cells can undergo self-destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti-apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c-KIT/SCF. The latter include Bcl-2, Bcl-X(L), Mcl-1, NF-(K)B, survivin, livin, and ML-IAP. Alternatively, some molecules such as TRAF-2, c-Myc, endothelins, and integrins may have either pro- or anti-apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl-1 and Bcl-X(L), which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF-(K)B, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research.
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PMID:Apoptosis and melanoma: molecular mechanisms. 1451 53

SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
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PMID:Effect of imatinib on haematopoietic recovery following idarubicin exposure. 1496 Oct 27

Imatinib mesylate (imatinib) is an orally administered competitive inhibitor of the tyrosine kinases associated with the KIT protein (stem cell factor receptor), ABL protein and platelet-derived growth factor receptors. The KIT tyrosine kinase is abnormally expressed in gastrointestinal stromal tumour (GIST), a rare neoplasm for which there has been no effective systemic therapy. In a randomised, nonblind, multicentre study that evaluated imatinib 400 or 600mg once daily in 147 patients with advanced GIST, confirmed partial responses were achieved in 54% of patients overall (median duration of follow-up was 288 days). Stable disease was experienced by 28% of patients and the estimated 1-year survival rate was 88%. Similar response rates were reported in a smaller, dose-escalation study, in which objective tumour response was a secondary endpoint. Although nearly all patients with GIST treated with imatinib experienced adverse events, most events were mild or moderate in nature. Severe or serious adverse events occurred in 21% of patients in the larger study, and included gastrointestinal or tumour haemorrhage. The control of cellular processes, such as cell growth, division and death, involves signal transduction, which commonly involves the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. Activation of oncogenes coding for kinase proteins can lead to the production of kinases that are continually active in the absence of a normal stimulus,leading to increased cell proliferation and/or decreased apoptosis. A major focus of cancer research in recent years has been to identify oncogenic molecules and the signal transduction pathways in which they are involved, in order to develop specifically targeted drugs. One such drug is imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2-phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine kinases associated with platelet-derived growth factor (PDGF) receptors, the Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF] receptor). Imatinib was initially evaluated for the treatment of chronic myeloid leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been approved for the treatment of patients with advanced gastrointestinal stromal tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed. GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal cells. They are rare neoplasms, with between 5000 and 10 000 new cases being diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract but the stomach and small intestine are the most common sites. Symptoms depend on the site and size of the tumour, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumours may be asymptomatic. The diagnosis of GIST is made by immunohistochemical staining for CD117, a cell surface antigen on the extracellular domain of KIT, in conjunction with pathological examination of tissue with light microscopy. All GISTs may have some degree of malignant potential. They are unresponsive to standard chemotherapy and to radiotherapy, and the mainstay of treatment in the past has been surgery. However, recurrence rates are high, and there has been no effective systemic treatment for unresectable GIST or metastatic disease. For patients in whom complete resection is not possible, or in patients with metastatic or recurrent disease, the median duration of survival is 9-12 months, and 10-19 months, respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to 90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto-phosphorylation of tyrosine residues independent of ligand-receptor binding), leading to aberrant cell division and tumour growth. Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for evaluating its effects in GIST. Subsequent to initial evidence of the clinical efficacy of imatinib in a single patient with progressive, metastatic, CD117-positive GIST, formal studies of imatinib in this new indication were initiated. This article summarises the pharmacology, efficacy and tolerability profile of imatinib in the treatment of patients with advanced GIST.
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PMID:Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. 1260 Feb 28

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.
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PMID:Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. 1468 12

Inflammatory fibroid polyps (IFPs) are rare mesenchymal tumors of the gastrointestinal tract that consist of spindle-shaped stromal cells and an inflammatory infiltrate rich in eosinophils. Their etiology and histogenesis remain unknown. Based on previous reports of their immunoreactivity for CD34 and c-kit biomarkers, IFPs have been thought to be related to gastrointestinal stromal tumors (GISTs). After reviewing the current literature and examining IFPs at the light microscopic level, we evaluated a series of IFPs using an extensive panel of immunohistochemical and in situ hybridization markers in an effort to gain insight into their etiology and histogenesis and to determine their true relationship to GISTs. Sixteen routinely processed IFP specimens (14 gastric, 1 ileal, and 1 rectal) were immunohistochemically stained for antibodies to CD34, HMB-45, desmin, smooth muscle actin, calponin, h-caldesmon, anaplastic lymphoma kinase, S-100 protein, epithelial membrane antigen, c-kit (CD117), stem cell factor (SCF/N19 or kit ligand), p53, bcl-2, cyclin D1, and human herpesvirus-8 (HHV8). In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was also performed. Ten cases were further evaluated for the dendritic cell markers fascin, CD21, CD23, and CD35. Stromal cells were diffusely positive for CD34 and fascin in all (100%) cases, and these stromal cells were, in addition, immunoreactive for calponin and smooth muscle actin in 88% and 25% of cases, respectively. CD35 was also found to be focally reactive in the stromal cells. Cyclin-D1 was overexpressed in all (100%) IFPs. All other immunohistochemical markers and EBER were negative in the stromal cells. These findings suggest that the proliferating stromal cells in IFPs are of dendritic cell origin, with some cases also exhibiting myofibroblastic features. Absence of c-kit, SCF, and h-caldesmon immunoreactivity fails to support a relationship to GISTs. We also conclude that Epstein Barr virus and HHV8 are unlikely etiologic agents of IFPs. Overexpression of cyclin D1 in all cases suggests that a defect in cell-cycle regulation may be involved in the growth of IFPs.
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PMID:Inflammatory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cell origin. 1470 72

Specific protein degradation has been observed in several aspects of development and differentiation in many organisms. One example of such proteolysis is regulated by protein polyubiquitination that is promoted by the SCF complex consisting of Skp1, cullin, and an F-box protein. We examined the activities of the Arabidopsis Skp1-related proteins (ASKs). Among 19 annotated ASK genes, we isolated 16 of the corresponding cDNAs (ASK1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19), and examined their gene products for interactions with 24 representatives of F-box proteins carrying various classes of the C-terminal domains using the yeast two-hybrid system. As a result, we found diverse binding specificities: ASK1, ASK2, ASK11 and ASK12 interacted well with COI1, FKF1, UFO-like protein, LRR-containing F-box proteins, and other F-box proteins with unknown C-terminal motifs. We also observed specific interaction between F-box proteins and ASK3, ASK9, ASK13, ASK14, ASK16 and ASK18. In contrast, we detected no interaction between any of the 12 ASK proteins and F-box proteins containing CRFA, CRFB or CRFC domains. Both histochemical and RT-PCR analysis of eight ASK genes expression revealed unique expression patterns for the respective genes.
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PMID:Expression and interaction analysis of Arabidopsis Skp1-related genes. 1474 89

The regulation of protein stability by the ubiquitin-proteasome pathway is a critical issue central to the comprehension of the molecular basis of carcinogenesis. However, ubiquitin modification of target substrates signals many cellular processes other than proteolysis that are also important for the development of cancer. It is noteworthy that many proteins studied by clinical breast cancer researchers are involved in these ubiquitin pathways. This review summarizes recent works on such proteins including cyclins, CDK inhibitors, and the SCF in cell cycle control; the breast and ovarian cancer suppressor BRCA1-BARD1; ErbB2/HER2/Neu and its ubiquitin ligase c-Cbl or CHIP; and the estrogen receptor and its downstream target Efp. Understanding these pathways may provide some hints toward developing diagnostic tools and treatments for breast cancer patients.
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PMID:Ubiquitin and breast cancer. 1502 95


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