Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.02 seconds)

Protein tyrosine phosphorylation plays an important role in cell growth, development and oncogenesis. No classical protein tyrosine kinase has hitherto been cloned from plants. Does protein tyrosine kinase exist in plants? To address this, we have performed a genomic survey of protein tyrosine kinase motifs in plants using the delineated tyrosine phosphorylation motifs from the animal system. The Arabidopsis thaliana genome encodes 57 different protein kinases that have tyrosine kinase motifs. Animal non-receptor tyrosine kinases, SRC, ABL, LYN, FES, SEK, KIN and RAS have structural relationship with putative plant tyrosine kinases. In an extended analysis, animal receptor and non-receptor kinases, Raf and Ras kinases, mixed lineage kinases and plant serine/threonine/tyrosine (STY) protein kinases, form a well-supported group sharing a common origin within the superfamily of STY kinases. We report that plants lack bona fide tyrosine kinases, which raise an intriguing possibility that tyrosine phosphorylation is carried out by dual-specificity STY protein kinases in plants. The distribution pattern of STY protein kinase families on Arabidopsis chromosomes indicates that this gene family is partly a consequence of duplication and reshuffling of the Arabidopsis genome and of the generation of tandem repeats. Genome-wide analysis is supported by the functional expression and characterization of At2g24360 and phosphoproteomics of Arabidopsis. Evidence for tyrosine phosphorylated proteins is provided by alkaline hydrolysis, anti-phosphotyrosine immunoblotting, phosphoamino acid analysis and peptide mass fingerprinting. These results report the first comprehensive survey of genome-wide and tyrosine phosphoproteome analysis of plant STY protein kinases.
Plant Mol Biol 2006 Jan
PMID:Genome-wide analysis and experimentation of plant serine/ threonine/tyrosine-specific protein kinases. 1642 65

Chronic myeloid leukemia (CML) originates from the hematopoietic stem cell and is characterized by the reciprocal translocation t(9;22)(q34;q11), which results in the BCR-ABL fusion gene on chromosome 22q-, also known as the Philadelphia chromosome. This chimeric gene codes for a cytoplasmic protein with constitutive tyrosine-kinase activity, responsible for cellular transformation and leukemogenesis in CML. The aim of this observational cohort study was to discriminate and quantify BCR-ABL transcripts in the peripheral blood of patients with CML who were treated with imatinib mesylate (Glivec, Novartis). Twenty-two patients were followed for six months during treatment. Quantitative real time polymerase chain reaction was performed before treatment and after 3 and 6 months from treatment initiation. As compared with the third month, there was a significant decrease in BCR-ABL expression in the sixth month of treatment (P = 0.0002). At the sixth month, there was a significant difference in the levels of the two major transcripts of BCR-ABL, B2A2 and B3A2 (P = 0.0347), indicating that B2A2 may be more sensitive to imatinib. The results of our study indicate that imatinib is able to modify the natural history of CML, and raise the hypothesis that patients who express the B2A2 transcript may have a better prognosis.
Genet Mol Res 2005 Dec 30
PMID:Differential molecular response of the transcripts B2A2 and B3A2 to imatinib mesylate in chronic myeloid leukemia. 1647 28

Real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR) methods for the quantitation of BCR-ABL mRNA in the blood of patients with chronic myeloid leukemia (CML) has become the predominant molecular monitoring technique. The BCR-ABL fusion gene is expressed in over 95% of patients with CML, and RQ-PCR provides a reliable, high-throughput method to accurately assess the level of treatment response and provides an early indication of emerging drug resistance. The ABI Prism 7700 Sequence Detection System uses TaqMan fluorogenic probes to quantitate specific nucleic acid sequences using RQ-PCR. The analyzer monitors an increase in fluorescence during the PCR cycle, which is proportional to the amount of accumulated product. The starting copy number is calculated relative to a series of standards. The copy number is normalized to a control gene that compensates for variations in the efficiency of the RT step and for the degree of RNA degradation. In our experience, reliable and consistent RQ-PCR requires thorough validation of all aspects of the procedure, including the selection of an appropriate control gene, careful assay design to avoid polymorphisms in primer or probe binding sites and to exclude the amplification of contaminating DNA, and monitoring the performance of the RQ-PCR by the use of quality control samples.
Methods Mol Med 2006
PMID:Diagnosis and monitoring of chronic myeloid leukemia by qualitative and quantitative RT-PCR. 1650 78

The major mechanism of imatinib resistance for patients with chronic myeloid leukemia (CML) is clonal expansion of leukemic cells with mutations in the Bcr-Abl fusion tyrosine kinase that reduce the capacity of imatinib to inhibit kinase activity. The early detection of such mutations may allow timely treatment intervention to prevent or overcome resistance. Direct sequencing of the BCR-ABL kinase domain is relatively rapid and allows detection of emerging mutations at a sensitivity of approx 20%. Mutations have been detected over a range of 242 amino acids, which spans the entire kinase domain. For optimal sensitivity, the kinase domain of the abnormal gene should be isolated by reverse-transcription (RT) polymerase chain reaction (PCR) amplification using primers that hybridize to the BCR and ABL genes. The quality of the RNA is assessed by real-time quantitative PCR prior to analysis, and BCR-ABL levels are determined. Only RNA of adequate quality is used to ensure accurate and reproducible mutation analysis. Depending on the level of BCR-ABL transcripts, a one- or two-step PCR is required to amplify the kinase domain. Direct sequencing with dye terminator chemistry is performed using PCR-purified products. The sequence is compared to an ABL kinase domain reference sequence using sequencing analysis software, which aligns the sequences and highlights single or multiple mutations.
Methods Mol Med 2006
PMID:Detection of BCR-ABL mutations and resistance to imatinib mesylate. 1650 79

With the development of fluorescence in situ hybridization (FISH), it was possible to detect the BCR-ABL fusion signal in both metaphase spreads and interphase cells of patients with chronic myeloid leukemia (CML). However, the use of FISH to detect residual disease in patients with CML post therapy was limited by the false positive rate using the early single fusion probes. Therefore, dual fusion probes that created a fusion signal on the derivative chromosome 9 in addition to the fusion sifnal on the Philadelphia chromosome or derivative chromosome 22 were developed. Using these second-generation probes, it was discovered that a significant proportion of CML cases has a sub-microscopic deletion at the site of the ABL-BCR fusion. This chapter outlines a testing strategy to identify deleltions of the derivative chromosome 9 and to use combinations of probes to identify residual disease in these cases.
Methods Mol Med 2006
PMID:Deletion of the derivative chromosome 9 in chronic myeloid leukemia. 1650 80

STI571 is a specific inhibitor of tyrosine kinases, such as BCR-ABL, platelet-derived growth factor receptor, and c-KIT, and has recently been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). This study demonstrated that STI571 induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1. In these cells, STI571 induced pro-caspase-12 or pro-caspase-7 cleavage and it affected caspase-3 activity and induced the endoplasmic reticulum (ER)-resident chaperone, glucose-regulated protein 78. The STI571-induced cell death was blocked by the protein synthesis inhibitor, cycloheximide. Together, these results suggest that STI571 induces cell death in GIST-T1 cells, at least in part, via the ER stress response.
Int J Mol Med 2006 May
PMID:STI571 (Glivec) induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1, via endoplasmic reticulum stress response. 1659 77

Universal Russian reagents for real time PCR were tested and compared with reference reagents provided by foreign companies. Testing was carried out on plasmids with cloning fragments (DNA-standards) of cDNA with chimeric (fusion) gene PML-RARalpha. Values of amplification efficiency of Russian and foreign reagents were measured on samples with serial dilutions (30-300000 copies) of cloned cDNA fragments of PML-RARalpha and internal control gene ABL. Amplification efficiencies of Russian and foreign reagents were found to be close one to another. Russian universal reagent kit RealityTM and ABI TaqMan Core Reagent Kit have amplification efficiencies 1.919 and 1.929, and correlation coefficients of copy numbers PML-RARalpha0.999 and 0.996, respectively. These values were determined by construction of a standard curve. To verify these results we studied also the samples of cDNA from blood and bone marrow of patients with acute promyelocytic leukemia. All samples posses translocation t(15;17), and appropriate chimeric gene PML-RARalpha. copy number in 1 microg of total RNA was in range 5.86 x 10(4)-8.315 x 10(5) before chemotherapy. No symptoms of minimal residual disease were found after 3.5 months since chemotherapy - fusion gene PML-RARalpha was not detected by real time PCR method. These results are in agreement with clinical data. Our investigations tend to show that application of RealityTM reagent set in real timePCR experiments gives correct results and may be used in molecular oncodiagnostics.
Mol Biol (Mosk)
PMID:[Characterization of the universal Russian reagent sets for real-time PCR and its application for molecular oncodiagnostic]. 1663 76

Monitoring breakpoint cluster region-Abelson kinase (BCR-ABL) levels in patients treated for chronic myelogenous leukemia (CML) has become an integral part of patient management. Real-time reverse transcriptase-polymerase chain reaction is the method of choice for this purpose because of its high analytical sensitivity and reproducibility. Given the variation of RNA quality and quantity in clinical specimens, accurate quantitative assessment of BCR-ABL depends on normalization of the BCR-ABL signal to an appropriate internal reference. However, the controls used by different laboratories vary, and there is no clear consensus on an ideal reference due to limited investigations. In this study, we compared nine commonly used control genes for three criteria: mRNA abundance, levels in CML and non-CML cells, and their degradation kinetics in comparison with BCR-ABL. We found that beta-glucuronidase (GUSB) is the most suitable among the nine genes tested. Although ABL is most widely used, our data suggest that the amount of ABL is different in CML and non-CML cells. Moreover, ABL levels are regulated by cellular stress. These findings have a direct impact on current clinical laboratory practice and patient care because the use of a proper control gene affects the reported levels of BCR-ABL transcripts used for patient management decisions.
J Mol Diagn 2006 May
PMID:Molecular monitoring of chronic myelogenous leukemia: identification of the most suitable internal control gene for real-time quantification of BCR-ABL transcripts. 1664 10

The deregulated tyrosine kinase activity of BCR-ABL is necessary and sufficient to induce chronic myelogenous leukemia (CML). This observation has paved the way for the development of small-molecule inhibitors specifically targeting the kinase activity of the BCR-ABL protein. Indeed, the amazing success of imatinib has revolutionized the whole area of targeted cancer therapeutics. However, enthusiasm for the striking efficacy of imatinib has been tempered by the development of clinical resistance. In essentially all cases, resistance results from kinase domain mutations and/or overexpression of the BCR-ABL gene. To overcome resistance, several novel BCR-ABL inhibitors have been developed and are in clinical trials, though it is inevitable that resistance to second-generation inhibitors will occur as well. Nonetheless, kinases represent an attractive target for therapeutic intervention in several diseases and, at present, some 50 different kinase inhibitors are in clinical trials. We anticipate that resistance to these compounds will follow mechanisms similar to those observed with imatinib. Resistance mutations cause their effect either by direct steric hindrance to drug binding or by allosterically modulating kinase dynamics. This review highlights the principal mechanisms underlying point mutations from these two different classes to confer drug resistance.
Mol Diagn Ther 2006
PMID:Anticipating clinical resistance to target-directed agents : the BCR-ABL paradigm. 1666 5

Lauric acid serves as an endogenous substrate for the cytochrome P450 enzyme CYP4A11. A reverse-phase, high-performance liquid chromatography method is described for the quantification of 12-hydroxylauric acid formed enzymatically by incubation of 14C-labeled lauric acid with cDNA-expressed CYP4A11 or human liver microsomes. Analytical separation is achieved using a C18 column and a gradient of 30% acetonitrile and 2 mM perchloric acid to 100% methanol, using a detection scintillation counter. This method is applicable to enzymatic studies for determination of lauric acid 12-hydroxylation activity.
Methods Mol Biol 2006
PMID:Determination of CYP4A11-catalyzed lauric acid 12-hydroxylation by high-performance liquid chromatography with radiometric detection. 1671 85


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