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)

The management of chronic myelogenous leukemia (CML) has become complex due to the availability of improved diagnostic procedures and life-prolonging or even curative treatment strategies that are more successful the earlier they are applied in the course of the disease. This is true for allogeneic bone-marrow transplantation, treatment with interferon alpha (IFN) and Philadelphia-negative stem-cell collections for autografting. Outcome differs according to risk profiles of patients at diagnosis. In addition, molecular techniques for the detection of the BCR-ABL fusion gene or its products, such as the reverse-transcriptase polymerase chain reaction (PCR), Southern blot analysis, or fluorescence in situ hybridization, facilitate accurate diagnosis and the monitoring of residual disease. They allow the individualization of treatment such as early infusion of donor lymphocytes if molecular relapse is detected after allografting, or discontinuation of IFN in the presence of very low BCR-ABL transcript levels). The availability of real-time PCR devices further improves and accelerates the diagnosis and monitoring of residual disease. This article addresses recent developments in drug therapy and allografting, including treatment intensification with low-dose ara C or intensive chemotherapy followed by autografting, introduction of new drugs (such as homoharringtonine or tyrosine kinase inhibitor STI571), progress with unrelated donor transplantations, use of peripheral blood stem cells for allografting, and transplantation without myeloablative conditioning. Tradeoffs between the treatment options will be discussed in the context of the evidence-based guidelines for treating CML, as recently published by the American Society of Hematology. Finally, the new competence network on acute and chronic leukemias will be introduced.
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PMID:Current trends in the management of chronic myelogenous leukemia. 1096 82

IMP dehydrogenase is a rate-limiting enzyme involved in the synthesis of GTP. In mammalian cells it is regulated with respect to growth rate and is the target of numerous therapeutic agents. Mutations in the RNA polymerase II elongation machinery render yeast sensitive to inhibitors of IMP dehydrogenase and defective in inducing transcription of one of the IMP dehydrogenase-encoding genes, IMD2. Here we show that loss of IMD2, but not IMD1, IMD3, or IMD4, conferred upon yeast the same drug sensitivity found in elongation mutants. We tested whether the drug sensitivity of elongation mutants is due to their inability to induce IMD2 by providing them with exogenous copies of the gene. In some elongation mutants, overexpression reversed drug sensitivity and a transcriptional defect. Overexpression in mutants with a more severe phenotype partially suppressed drug sensitivity but was inconsequential in reversing a defect in transcription. These findings suggest that the drug sensitivity of elongation mutants is largely but not solely attributable to defects in the ability to induce IMD2, because transcription is compromised even when IMD2 mRNA levels are adequate. We describe two DNA sequence elements in the promoter of the gene that regulate it. We also found that IMD2 mRNA abundance is coupled to cell growth rate. These findings show that yeast possess a conserved system that gauges nucleotide pools and cell growth rate and responds through a uniquely regulated member of the IMD gene family.
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PMID:Regulation of an IMP dehydrogenase gene and its overexpression in drug-sensitive transcription elongation mutants of yeast. 1144 Oct 18

There is a need to investigate the mechanistic basis of the human skin irritation response if relevant in vitro test systems for the predictive identification of skin irritation hazards are to be developed. Recent progress in genomics technologies mean that tools for the identification and investigation of important biochemical events in the processes of skin irritation are now available. The aim of this work was to identify genes (for further mechanistic investigation) which may be regulated in response to skin irritation, following exposure of the EpiDerm skin model to the known skin irritant sodium lauryl sulphate (SLS). EpiDerm cultures were treated in triplicate with a non-cytotoxic dose of SLS (0.1 mg/ml, as determined by the MTT assay and histological examination) for 15 min, 30 min, 1 h, 2 h, 3 h, 4 h and 24 h. Total RNA was extracted from the pooled EpiDerm cultures and used to probe Atlas human arrays (Clontech) covering approximately 3600 genes. Preliminary data indicated an up-regulation at early time points (15-30 min) of a number of genes involved in transportation (e.g. the sodium and chloride dependent taurine transporter) and receptors (e.g. ZAP70 and protocadherin 42 precursor). The gene encoding the UV excision repair protein and other DNA repair genes (e.g. DNA-directed RNA polymerase II) were up-regulated after 1-3 h, along with TGF beta 3 and other tumour suppressors, which play a role in cellular development and wound healing. At the later time points of 4-24 h, genes involved in protein translation (e.g. Cathepsin D receptor) and metabolism (e.g. CYP27A) were up-regulated. In addition, a number of genes were down-regulated in response to treatment with SLS, although these followed less of a time dependent pattern. These results indicate the differential regulation of a number of genes in response to treatment with SLS, some of which may provide additional clues to the molecular events underpinning the irritation response to this particular surfactant and possibly to other chemical irritants.
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PMID:Gene expression analysis of EpiDerm following exposure to SLS using cDNA microarrays. 1156 69

Transcriptional regulation by estrogen receptor alpha (ERalpha) involves protein-protein interactions among the receptor, its associated coactivators and the RNA polymerase II transcriptional machinery. We have used an in vitro chromatin assembly and transcription system to examine the biochemistry of interactions among ERalpha, the SRC proteins and p300/CBP. Using polypeptides designed to block specific receptor- cofactor or cofactor-cofactor interactions, we show that interactions among ERalpha, its coactivators and the RNA pol II machinery are all required for ERalpha- mediated transcription. Furthermore, we show that ERalpha-SRC-p300/CBP interactions are necessary and sufficient for the targeted acetylation of nucleosomal histones on estrogen-responsive promoters in the absence of transcription. The protein-protein interactions required for histone acetylation constitute a subset of the interactions required for transcriptional activation. Finally, we show that the major role of SRC-p300/CBP interactions is to enhance ERalpha- mediated transcription initiation, and they have little or no role in stimulating subsequent rounds of transcription. Together, our results indicate a specific role for the SRC and p300/CBP coactivators, as well as targeted histone acetylation, in ERalpha-mediated transcription.
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PMID:A role for coactivators and histone acetylation in estrogen receptor alpha-mediated transcription initiation. 1168 48

A case of Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) with multiple subclones including duplication of the BCR-ABL1 fusion gene and of the Abelson oncogene (ABL1) is reported. Cytogenetically, two different rearrangements of chromosome 9 not involved in the t(9;22) were found in two subclones. In one subclone the normal 9 was lost and replaced by an acrocentric marker, which contained an additional copy of the BCR-ABL1 fusion gene. Reverse transcriptase polymerase chain reaction detected the fusion transcripts p210 (e13a2 junction) and p190 (e1a2 junction), whereas fluorescence in situ hybridization showed the major BCR-ABL1 junction in both Ph chromosomes, strongly suggesting that the presence of the p210 and p190 proteins in this case was due to mechanisms of alternative or mis-splicing at the transcriptional level. The second subclone showed the classic t(9;22) plus an add(9)(p24) containing two copies of the ABL1 gene. Other molecular events involving chromosome 9 were a monoallelic loss of JAK2 in both subclones and an additional loss of P15/P16 in the subclone with the acrocentric marker bearing the extra Ph chromosome.
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PMID:Philadelphia-positive acute lymphoblastic leukemia with multiple subclones including duplication of the Philadelphia chromosome and Abelson oncogene. 1180 8

SV(PZF) is a mutant of Sindbis virus (SV) which we selected on the basis of its ability to replicate in mosquito cells treated with pyrazofurin (PZF), a drug which inhibits pyrimidine nucleotide biosynthesis (Lin et al., 2000, Virology 272, 61-71). Three mutations, A6627U, A7543U, and C7593A, were identified in the nsP4 (the viral RNA polymerase) coding region, which were required for the PZF-resistant phenotype. We report here that SV(PZF) has a second phenotype. Its replication in BHK cells is severely restricted; yields of SV(PZF) from BHK cells are 100- to 1000-fold lower than the yields of standard SV (SV(STD)). However, addition of adenosine to the SV(PZF)-infected cultures completely relieves this restriction and results in yields comparable to those observed with SV(STD). Adenosine has no effect on the yield of SV(STD) from BHK cells. Synthesis of the viral structural proteins is markedly depressed in SV(PZF)-infected BHK cells, as is synthesis of the viral subgenomic (SG) RNA from which these proteins are translated. In contrast, normal amounts of genomic RNA are made. Experiments with mutagenized viruses indicated that the SV(PZF) mutation, C7593A, by itself, was sufficient to produce the restriction phenotype. However, this mutation not only changes Pro 609 of nsP4 to Thr, it also changes the nucleotide at the minus sign5 position of the SG promoter. To evaluate the relative contributions of the change in nsP4 and the change in the SG promoter to the restriction phenotype, we made use of double SG viruses, in which nsP4 and the promoter for the SG RNA which encodes the structural proteins can be changed independent of each other. Our results indicated that both the change in nsP4 and the change in the SG promoter were required to produce the full restriction phenotype. We suggest that the changes in nsP4 and the SG promoter destabilize the RNA initiation complex assembled at the SG promoter and that since ATP is the initiating nucleotide in the SG RNA transcript, the increased level of ATP resulting from the addition of adenosine is able to compensate for this destabilization and restore the synthesis of SG RNA to normal levels.
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PMID:Restriction of a Sindbis virus mutant in BHK cells and relief of the restriction by the addition of adenosine. 1187 10

Detection of BCR-ABL transcripts in chronic myeloid leukaemia (CML) is used to confirm the diagnosis and to monitor residual disease. Quantitative techniques are required to predict response to therapy or early relapse. We have evaluated an assay in which transcription-mediated amplification (TMA) of BCR-ABL and ABL transcripts is achieved using reverse transcriptase and RNA polymerase. The products are quantified in the hybridisation protection assay (HPA) using acridinium ester-labelled DNA probes and chemiluminescence. The method is a single tube procedure which uses small amounts of RNA (<500 ng/triplicate analysis), is technically simple (requiring just two waterbaths and a luminometer), rapid (total assay time <4 h) and sensitive (capable of detecting one BCR-ABL-positive K562 cell in the presence of 10(4)-10(5) BCR-ABL-negative cells). BCR-ABL signals from patient RNA samples were quantified relative to known amounts of K562 RNA and normalised to levels of ABL. BCR-ABL/ABL ratios ranged from 0.15 to 1.59 (median 0.65) in RNA from diagnostic blood or bone marrow of 18 CML patients and were < or =0.0001 in 20 normal controls. Sequential samples analysed from six CML patients post-allogeneic bone marrow transplantation who relapsed and received donor lymphocyte infusions showed BCR-ABL/ABL ratios which reflected patient status or treatment. A BCR-ABL/ABL ratio of 0.01 served as a useful arbitrary indicator value, with results above and below this value generally correlating with relapse or remission, respectively.
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PMID:Transcription-mediated amplification and hybridisation protection assay to determine BCR-ABL transcript levels in patients with chronic myeloid leukaemia. 1189 44

For patients with chronic myeloid leukaemia, methods for monitoring response to treatment have changed considerably in recent years. In the 1980s, the principal approach was repeated examination of bone marrow metaphases for the presence of the Ph chromosome in patients treated by interferon-alpha (IFN-alpha) or allogeneic stem cell transplantation. The use of fluorescence in situ hybridisation (FISH) techniques to detect the BCR-ABL fusion gene in Ph-positive leukaemia cells increased the sensitivity of cytogenetic studies to some degree. In the last 10 years, the reverse-transcriptase polymerase chain reaction (RT-PCR) has proved extremely valuable for assessing and monitoring minimal residual disease in patients who achieve Ph negativity after treatment with IFN-alpha or with the new Abl tyrosine kinase inhibitor imatinib mesylate or after allogeneic stem cell transplantation (SCT). Results are consistent with the notion that the majority of long-term survivors after allogeneic SCT are probably 'cured'; for other patients monitored serially in complete cytogenetic remission, rising numbers of BCR-ABL transcripts detected by RT-PCR can indicate the need for further therapy.
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PMID:Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia. 1191 87

The classification of chronic neutrophilic leukemia (CNL) is controversial. Our purpose was to correlate clinical, pathologic, and molecular analyses in 2 cases of CNL. In both cases, the patients were referred because of a substantially increased peripheral WBC count noted during routine examination. Bone marrow biopsies and aspirate smears revealed hypercellularity with myeloid/erythroid ratios of 4:1 and 11:1, respectively. The bone marrow aspirate results were as follows: case 1: blasts, 2%; promyelocytes, 2%; myelocytes, 6%; metamyelocytes, 16%; band neutrophils, 13%; segmented neutrophils, 34%; and case 2: blasts, 1%; promyelocytes, 2%; myelocytes, 15%; metamyelocytes, 20%; band neutrophils, 24%; neutrophils, 19%. Reverse transcriptase in situ polymerase chain reaction studies demonstrated expression of mu-BCR-ABL transcripts in 13% and 25% of the bone marrow cells, respectively. In both cases, the positive signal was noted mainly in the early granulocytic precursors and was present in occasional mature neutrophils. To our knowledge, this is thefirst in situ demonstration of mu-BCR-ABL expression in CNL Ourfindings reinforce the usefulness of this messenger RNA as a molecular marker of CNL.
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PMID:Expression of mu-BCR-ADL transcripts in chronic neutrophilic leukemia. 1247 76

The role of T cells in eradicating leukemic cells has been well demonstrated for chronic myeloid leukemia (CML). Type 1 (T1) T-cell cytokines play a major role in this antileukemic immune effect. Studies in cancer patients have demonstrated a decreased T1 cytokine production, measured by enzyme-linked immunosorbent assay (ELISA), in cultures of peripheral blood mononuclear cells. This observation of malignancy-related suppressed T1 cytokines also occurs in untreated chronic-phase (CP) CML, raising the question of the influence of different CML treatment regimens on this immunosuppression. Intracellular flow cytometry (ICF) has facilitated the evaluation of cytokines on a single-cell level. This study analyzed T1 (interferon-gamma) cytokine production in purified peripheral blood T cells by ICF, comparing different therapy approaches for CML. Twenty-one newly diagnosed CP CML patients were compared with 24 patients treated with interferon-alpha (IFN-alpha) and to 30 allogeneic bone marrow transplant (BMT) recipients (BCR-ABL negative by reverse-transcriptase polymerase chain reaction, and free of, or having only limited graft-versus-host disease at the time of study). Thirty-seven healthy controls were included. Our results showed a significantly decreased T-cell IFN-gamma synthesis in CP CML patients in relation to healthy controls (P = 0.0007). Treatment with IFN-alpha resulted in a shift from immunosuppression--documented for the group of untreated patients--to immunopotentiation, with an increase of T-cell IFN-gamma production (P = 0.0266). Notably, BMT enhanced IFN-gamma production of T cells to a level not only exceeding untreated patients (P < 0.0001) but also healthy volunteers (P < 0.0001). The observation of T1 cytokine up-regulation with IFN-alpha therapy indicates that enhanced T-cell function may be achievable in patients with CML, even in the absence of an allo-response.
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PMID:Intracellular cytokine analysis of interferon-gamma in T cells of patients with chronic myeloid leukemia. 1260 98


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