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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinases have emerged as a major drug target in the last years. Since more than 500 kinases are encoded in the human genome, cross-reactivity of a majority of kinase inhibitors causes problems. Tools are required for a rapid classification of inhibitors according to their affinity for a certain target to refine the search for new, more specific lead compounds. Mass spectrometry (MS) is increasingly used in pharmaceutical research and drug discovery to investigate protein-ligand interactions and determination of binding affinities. We present a comparison of different existing nanoelectrospray-MS based methods to quantify binding affinities and qualitatively rank, by competitive experiments, the affinity of several clinical inhibitors. We also present a new competitive method which is derived from our previous work for quantitative assessment of binding strengths (Wortmann et al., J. Mass Spectrom. 2008, 43(5), 600-608). The human kinases studied for this purpose were p38alpha (MAPK14) and LCK (lymphocyte specific kinase), and their interaction with 17 known small molecule kinase inhibitors was probed. Moreover, we present a new method to differentiate type I from type II inhibitors (Liu, Y.; Gray, N. S. Nat. Chem. Biol. 2006, 2(7), 358-364) based on a kinetic experiment with direct MS read-out of the noncovalent complex between the human kinase and the inhibitor. This method was successfully applied to p38alpha binding to BIRB796, as well as to a BIRB796 analogue. Quantitative determination of the binding strength is also described. The results of our competitive experiments for the affinity classification of different inhibitors, as well as the results for the kinetic study, are in good agreement with IC(50) measurements and data found in the literature.
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PMID:Affinity classification of kinase inhibitors by mass spectrometric methods and validation using standard IC(50) measurements. 1906 73

Calcium modulating cyclophilin ligand (CAML) is a ubiquitously expressed cytoplasmic protein that is implicated in the EGFR and LCK signaling pathways and required for early embryonic and thymocyte development. To further define the critical biological functions of CAML at the cellular level, we generated CAML-deleted mouse embryonic fibroblasts (MEFs) using an in vitro Cre-loxP mediated conditional knockout system. We found that CAML(-/-) MEFs have severely impaired proliferation and a strong reduction of normal anaphases. The primary mitotic defect of CAML(-/-) MEFs is that duplicated chromosomes fail to segregate in anaphase, resulting in nuclear bisection by the cleavage furrow as cells decondense their DNA and exit mitosis, highly reminiscent of the "cut" phenotype in fission yeast. This phenotype is due to spindle dysfunction rather than inability to resolve physical connections between sister chromatids. Furthermore, CAML(-/-) MEFs display defects often seen in cells with mitotic checkpoint gene deficiencies, including lagging and misaligned chromosomes and chromatin bridges. Consistent with this, we found that CAML(-/-) MEFs have a modestly weakened spindle assembly checkpoint (SAC) and increased aneuploidy. Thus, our data identify CAML as a novel chromosomal instability gene and suggest that CAML protein acts as a key regulator of mitotic spindle function and a modulator of SAC maintenance.
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PMID:CAML loss causes anaphase failure and chromosome missegregation. 1922 38

A laboratory scale anaerobic migrating blanket reactor (AMBR) reactor was operated at nitrobenzene (NB) loading rates increasing from 3.33 to 66.67 g NB/m(3)day and at a constant hydraulic retention time (HRT) of 6 days to observe the effects of increasing NB concentrations on chemical oxygen demand (COD), NB removal efficiencies, bicarbonate alkalinity, volatile fatty acid (VFA) accumulation and methane gas percentage. Moreover, the effect of an aerobic completely stirred tank reactor (CSTR) reactor, following the anaerobic reactor, on treatment efficiencies was also investigated. Approximately 91-94% COD removal efficiencies were observed up to a NB loading rate of 30.00 g/m(3)day in the AMBR reactor. The COD removal efficiencies decreased from 91% to 85% at a NB loading rate of 66.67 g/m(3)day. NB removal efficiencies were approximately 100% at all NB loading rates. The maximum total gas, methane gas productions and methane percentage were found to be 4.1, 2.6l/day and 59%, respectively, at a NB loading rate of 30.00 g/m(3)day. The optimum pH values were found to be between 7.2 and 8.4 for maximum methanogenesis. The total volatile fatty acid (TVFA) concentrations in the effluent were 110 and 70 mg/l in the first and second compartments at NB loading rates as high as 66.67 and 6.67 g/m(3)day, respectively, while they were measured as zero in the effluent of the AMBR reactor. In this study, from 180 mg/l NB 66 mg/l aniline was produced in the anaerobic reactor while aniline was completely removed and transformed to 2mg/l of cathechol in the aerobic CSTR reactor. Overall COD removal efficiencies were found to be 95% and 99% for NB loading rates of 3.33 and 66.67 g/m(3)day in the sequential anaerobic AMBR/aerobic CSTR reactor system, respectively. The toxicity tests performed with Photobacterium phosphoreum (LCK 480, LUMIStox) and Daphnia magna showed that the toxicity decreased with anaerobic/aerobic sequential reactor system from the influent, anaerobic and to aerobic effluents.
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PMID:Effect of increasing nitrobenzene loading rates on the performance of anaerobic migrating blanket reactor and sequential anaerobic migrating blanket reactor/completely stirred tank reactor system. 1928 17

Translocations of proto-oncogenes to the B-cell or T-cell antigen receptor loci in acute T- or B-cell leukemia and lymphoma have been, in most cases, accredited to V(D)J or switch recombination depending on the location of the breakpoint at the receptor locus. Only in rare instances, the reports take into account mechanistic characteristics of the translocation mechanism. To assess the functional ability of several sites implicated in supposedly V(D)J-mediated translocations, we tested five sites at four proto-oncogene loci in an ex vivo recombination substrate assay for their potential to act as direct target for V(D)J recombination. Our results show that the LMO2/RBTN2/TTG2 site and one LCK/P56 site readily engage in recombination with a genuine TCR element with the majority of breakpoint junctions showing the characteristics of V(D)J recombination, which strongly supports the involvement of this mechanism in the pathogenesis of the corresponding translocations in vivo. The site at the TLX1/HOX11 locus yielded 0.8% V(D)J-specific junctions. Sites at the LCK/P56 and TCF3/E2A proto-oncogenes resulted in exclusively unspecific breakpoints scattered over part of or the entire proto-oncogene region tested, marking them as unlikely V(D)J recombination targets. Our data suggest that, while being a potentially dangerous mechanism due to the introduction of DNA breaks, V(D)J recombination is a tightly controlled mechanism allowing for only few direct mistakes.
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PMID:V(D)J targeting mistakes occur at low frequency in acute lymphoblastic leukemia. 1945 8

The EGFR pathway is a critical signaling pathway deregulated in many solid tumors. In addition to the initiation and progression of cancer, the EGFR pathway is also implicated in variable treatment responses and prognoses. Genetic variation in the form of Single Nucleotide Polymorphisms (SNPs) can affect the function/expression of the EGFR pathway genes. Here, we applied a systematic and comprehensive approach utilizing diverse public databases and in silico analysis tools to select putative functional genetic variations from 244 genes involved in the EGFR pathway. Our data comprises 649 SNPs. Three hundred sixty SNPs are predicted to have biological consequences (functional SNPs). These SNPs can be directly used in further studies to test their association with risk, treatment response and prognosis in cancer. To systematically cover the EGFR pathway, we also performed a network-based analysis to further select putative functional SNPs from the genes whose protein products physically interact with the EGFR pathway proteins. We utilized protein-protein interaction information and focused on 14 proteins that have a high degree of connectivity (interacting with > or = 10 proteins) with the EGFR pathway genes identified to have functional SNPs (f-EGFR genes). Two of these proteins (FYN and LCK) had interactions with 17 of the f-EGFR genes, yet both lacked any putative functional SNP. However, our analysis indicated the presence of potentially functional SNPs in 9 other highly interactive proteins. The genes and their SNPs identified in the network-based analysis represent potential candidates for gene-gene and SNP-SNP interaction studies in cancer research.
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PMID:A comprehensive catalogue of functional genetic variations in the EGFR pathway: protein-protein interaction analysis reveals novel genes and polymorphisms important for cancer research. 1949 47

The aim of this exploratory work was to use a microarray-based approach to study the global transcriptome profile of caesarean-derived, colostrum-deprived (CDCD) piglets experimentally infected with porcine circovirus type 2 (PCV2). PCV2-inoculated piglets developed a subclinical infection, as confirmed by serology, in situ hybridization and quantitative PCR. Total RNA from mesenteric lymph nodes and lungs was obtained by duplicate from 2 control and 2 PCV2-inoculated piglets and was hybridized to Affymetrix Porcine GeneChip. Among the 24,123 probesets studied, 25 and 33 were found to be significantly differentially expressed (DE) between control and PCV2 groups for mesenteric lymph node and lung, respectively. Most up-regulated genes in PCV2 group were closely related to the immune response, such as cytokines (CCL4L, CXCL9, CXCL11), MHC binding molecules (TCRalpha, CD8alpha), immunoglubulins (IgG) and T cell activation (LCK, KLRK1, RASSF2, GBP2). Quantitative real-time PCR was performed to verify the microarray results. Therefore, from a transcriptional point of view, PCV2-inoculated pigs were apparently able to activate a cell-mediated response and develop PCV2-specific antibodies, which probably led to a subclinical infection. The results from this study indicate that a microarray based approach is a helpful tool in order to better understand the pathogenesis of PCV2 infection.
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PMID:Exploratory study on the transcriptional profile of pigs subclinically infected with porcine circovirus type 2. 1954 6

The cytoplasmic tail of mammalian CD8alpha binds the kinase LCK in a zinc-dependent manner. In analogy with a previous study for humans (Kim et al., 2003) peptides were synthesized from rainbow trout CD8alpha and LCK. Surface plasmon resonance (SPR) analysis indicated that also in fish these molecules bind to each other in a zinc-dependent manner.
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PMID:Zinc-dependent binding between peptides derived from rainbow trout CD8alpha and LCK. 1981 7

Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.
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PMID:Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. 2030 34

Age-related changes of gene expression contribute to the physiological alteration observed with human ageing. Herein, the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of healthy young to middle-age probands (35.0 +/- 6.5 year old) and healthy old probands (82.5 +/- 6.8 year old). This study provides a list of 16 differentially abundant transcripts species in the healthy old probands. Thus, these changes of abundance can be considered as easily accessible biomarkers of ageing. Some of these differential abundances like CD28, CD69, LCK (decreased abundance in old subjects), CD86, Cathepsin D, H and S (increased abundance in old subjects) might explain biochemical and cytochemical changes observed at the protein level in the immune system and thus might correspond to regulatory processes affecting the ageing process. Indeed these changes reflect the low-grade pro-inflammatory status observed in old persons and suggest a hypo-responsiveness of T-cells together with an increase in antigen presentation potential. In addition, among the differentially abundant transcripts were transcripts involved in the oxidative stress response HMOX1 and HSPA6 mRNAs were found as more abundant in PBMC from elderly subjects.
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PMID:Transcriptomic biomarkers of human ageing in peripheral blood mononuclear cell total RNA. 1999

Dasatinib, (former BMS 354825), is an orally available small-molecule multikinase inhibitor. It potently inhibits BCR-ABL and SRC-family kinases (SRC, LCK, YES, FYN), but also c-KIT, PDGFR-alpha and beta, and ephrin receptor kinase.Dasatinib is about 300 times more potent than imatinib in cells expressing unmutated BCR-ABL in vitro. The drug has demonstrated activity against clinically relevant mutations, including those associated with poor prognosis during ongoing imatinib therapy.Dasatinib is approved for the treatment of patients with BCR-ABL-positive chronic myeloid leukemia (CML), resistant or intolerant to imatinib in chronic, accelerated, and blast phase. It also is approved for the treatment of Philadelphia Chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) resistant or intolerant to imatinib.A single daily dose of 100 mg in chronic phase CML results in high hematologic and molecular remission rates and prolongation of survival. In accelerated and blastic phase as well as in ALL, 70 mg twice daily is recommended. Complete hematologic and cytogenetic remissions (CR) frequently occur even in this patient group with poor prognosis. Remissions however are very short.Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. The role of dasatinib in other diseases, including solid tumors, has to be identified.
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PMID:Dasatinib. 2007 33


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