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 three genes hTAF(II)68, EWS, and TLS (called the TET family) encode related RNA binding proteins containing an RNA recognition motif and three glycine-, arginine-, and proline-rich regions in the C-terminus and a degenerated repeat containing the consensus sequence Ser-Tyr-Gly-Gln-Ser in the N-terminus. In many human cancers, the N-terminal portion of hTAF(II)68, EWS, or TLS is fused to the DNA binding domain of one of several transcription factors including Fli-1, ERG, ETV1, E1AF, WT1, ATF-1, CHOP, or TEC. We have recognized the presence of several potential tyrosine phosphorylation sites within the amino-terminal domain of hTAF(II)68 and have investigated the potential effects of cytoplasmic signaling on hTAF(II)68 function. Herein, we find that hTAF(II)68 is phosphorylated on tyrosine residue(s) by ectopic expression of v-Src protein tyrosine kinase in vitro and in vivo. The hTAF(II)68 protein can associated with the SH3 domains of several cell signaling proteins, including v-Src protein tyrosine kinase. We also document that full-length v-Src can stimulate hTAF(II)68-mediated transcriptional activation, whereas deletion mutants of v-Src are unable to exert this effect. In addition, cellular Src activity appears important for hTAF(II)68 function since hTAF(II)68-mediated transactivation is reduced in a dose-dependent fashion by ectopic overexpression of a dominant-negative mutant of Src. Taken together, our results suggest that the biological activities of hTAF(II)68 are linked to the cytoplasmic Src signal transduction pathway.
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PMID:Stimulation of hTAFII68 (NTD)-mediated transactivation by v-Src. 1509 65

Relapse postautograft in acute myeloid leukaemia (AML), may in part arise from leukaemia cells present in the bone marrow (BM) inoculum, and the level of minimal residual disease (MRD) in BM harvests used for autografting may therefore be clinically important. We have used the WT1 transcript as a marker of MRD, which was quantitated by RQ-PCR, in the BM harvests of 24 patients receiving an ABMT for AML. ABL was used as a control gene with WT1 level being normalised to 10(5) copies of ABL per sample. Median WT1 level was 651 copies (range=113-32 700) for the 13 patients with relapse-free survival (RFS) of less than 5 years, and 174 (range=0-1900) for patients with RFS of over 5 years postautograft (P<0.04). The RFS was 10.5 months for patients with WT1 level of >2000 copies (n=5), and has not yet been reached for patients with WT1 level<2000 (n=21), at a median follow-up of 92 months (P<0.05). We show that elevated levels of MRD in BM harvests are associated with a higher relapse risk in patients autografted for AML.
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PMID:Elevated levels of WT1 transcripts in bone marrow harvests are associated with a high relapse risk in patients autografted for acute myeloid leukaemia. 1590 82

Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
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PMID:Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. 1623 Mar 71

The PAXgene RNA blood collection tube is used for RNA of peripheral blood (PB) and the stability of PB RNA in this tube has already been reported. However, the stability of bone marrow blood (BM) RNA in the PAXgene tube is unknown. Thus, we examined the stability of BM RNA in the PAXgene tubes. BM from leukemia patients was collected into PAXgene and EDTA tubes and stored at 4 degrees C for 5 days. RNA isolated from both tubes was analyzed by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Porphobilinogen deaminase (PBGD) mRNA of BM (as high-expression mRNA) and Wilms tumor suppressor (WT1) mRNA of BM (as low-expression mRNA) and very low copies of major BCR-ABL mRNA (as minimal residual disease of leukemia) of leukemia of BM were quantified by a LightCycler system. RNA yield from the PAXgene tubes and the intensity of 28S rRNA bands on RNA electrophoresis showed a degradation trend. However, the intensity of 18S rRNA bands from the PAXgene tubes remained. The expression of PBGD and WT1 of BM in the PAXgene tubes did not decrease for 5 days. The very low copies of major BCR-ABL mRNA in the PAXgene tubes were detectable on day 5 but those in the EDTA tubes were not detectable. Therefore, the PAXgene tube can be used for BM samples in a quantitative RT-PCR of the fusion gene transcripts of leukemia.
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PMID:Examination of stability of bone marrow blood RNA in the PAXgene tube. 1695 Jun 75

This study was aimed at the characterization of a gene expression signature of the pluripotent hematopoietic CD34(+) stem cell in idiopathic myelofibrosis (IM), which would eventually provide novel pathogenetic insights and/or diagnostic/prognostic information. Aberrantly regulated genes were revealed by transcriptome comparative microarray analysis of normal and IM CD34(+) cells; selected genes were also assayed in granulocytes. One-hundred seventy four differentially expressed genes were identified and in part validated by quantitative polymerase chain reaction. Altered gene expression was corroborated by the detection of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IM CD34(+) cells. According to class prediction analysis, a set of eight genes (CD9, GAS2, DLK1, CDH1, WT1, NFE2, HMGA2, and CXCR4) properly recognized IM from normal CD34(+) cells. These genes were aberrantly regulated also in IM granulocytes that could be reliably differentiated from control polycythemia vera and essential thrombocythemia granulocytes in 100% and 81% of cases, respectively. Abnormal expression of HMGA2 and CXCR4 in IM granulocytes was dependent on the presence and the mutational status of JAK2(V617F) mutation. The expression levels of both CD9 and DLK1 were associated with the platelet count, whereas higher WT1 expression levels identified IM patients with more active disease, as revealed by elevated CD34(+) cell count and higher severity score. In conclusion, molecular profiling of IM CD34(+) cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.
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PMID:Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1). 1699 May 84

We carried out sequential molecular monitoring of different markers on two BCR-ABL positive ALL patients receiving a standard dose induction regimen, which was followed by a maintenance therapy that alternated imatinib and chemotherapy administration. Molecular study was performed at diagnosis, at the end of the induction phase, and then every three months during maintenance therapy. Each marrow sample underwent BCR-ABL analysis (p210 and p190 expression by RT-PCR and Real-time PCR) and monoclonal JH rearrangement analysis, while WT1 gene expression was detected by Real-time PCR. At diagnosis we detected high WT1 expression associated with the presence of both BCR-ABL transcripts and monoclonal JH rearrangement in both patients. Hematological remission, as well as a molecular status characterized by undetectable BCR-ABL expression, normal levels of WT1 expression, and persistence of monoclonal JH rearrangement, were achieved by both patients post-therapy. Follow up of patient 1 showed a progressive increase in WT-1 and in p-190 transcript, which was followed by cytogenetic and hematological relapse. We observed a progressive increase in the p210 transcript without a concomitant increase in WT-1 levels in patient 2. JH rearrangement was detected in all the samples analyzed. The molecular results may indicate the persistence of JH rearranged clonal cells with undetectable BCR-ABL. From a clinical point of view, our preliminary experience suggests that simultaneous analysis of BCR-ABL, JH and WT-1 expression may improve the study of MRD in Ph+ ALL.
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PMID:Monitoring molecular response by BCR-ABL, JH and WT-1 in Ph+ all treated with imatinib containing regimen: preliminary report of two cases. 1716 71

The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced expression of WT1 in K562 cells provided protection against cytotoxic effects of the ABL1 tyrosine kinase inhibitor imatinib, as judged by effects on viability measured by trypan blue exclusion, metabolic activity, annexin V and DAPI (4', 6-diamidino-2-phenylindole) staining. None of the isoforms provided any detectable protection against apoptosis induced by arsenic trioxide and only very weak protection against etoposide, indicating that WT1 interferes with specific apoptotic signalling pathways. Our data demonstrate that WT1 expression is induced by oncogenic signalling from BCR/ABL1 and that WT1 contributes to resistance against apoptosis induced by imatinib.
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PMID:Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells. 1772 83

Secondary tumors and leukemias are major complications in Hodgkin lymphoma (HL). They likely arise from clonal selection of cells that have accumulated genomic lesions induced by chemo- and radiotherapy and may be further promoted by the loss of DNA repair and/or other pathways ensuring the fidelity of replicated DNA. To distinguish genomic imbalances associated with the development of acute myeloid leukemia (AML) in HL we used an array-based comparative genomic hybridization (aCGH) strategy on whole lymph node biopsies of HL patient. Genomic imbalances (amplifications and deletions) associated with AML outcome in 3 classic HL patients, at clinical diagnosis they exhibited a discrete individual variability. Three amplifications and 5 deletions were shared by all 3 patients. They involved AFM137XA11, a 9p11.2 pericentric region; FGFR1, the FGF receptor most frequently translocated in AML; PPARBP, a co-activator of nuclear receptors RARalpha, RXR and TRbeta1; AFM217YD10, a 17q25 telomeric region; FGR, an SRC2 kinase involved in cytokine production by NK and CD4+ NKT cells; GATA3, a Th2-specific transcription factor; TOP1, involved in DNA recombination and repair; WT1, a transcription factor involved in CD8+ T cell response against leukaemic blasts. Immunohistochemistry confirmed aCGH results and distinguished the distribution of either amplified or deleted gene products in neoplastic Reed Sternberg (RS) cells and non-neoplastic lymph node components.
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PMID:Genomic imbalances associated with secondary acute leukemias in Hodgkin lymphoma. 1798 26

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder, in which multiple genetic abnormalities cooperate in the malignant transformation of thymocytes. About 20% of pediatric T-ALL cases are characterized by TLX3 expression due to a cryptic translocation t(5;14)(q35;q32). Although a number of collaborating genetic events have been identified in TLX3 rearranged T-ALL patients (NOTCH1 mutations, p15/p16 deletions, NUP214-ABL1 amplifications), further elucidation of additional genetic lesions could provide a better understanding of the pathogenesis of this specific T-ALL subtype. In this study, we used array-CGH to screen TLX3 rearranged T-ALL patients for new chromosomal imbalances. Array-CGH analysis revealed five recurrent genomic deletions in TLX3 rearranged T-ALL, including del(1)(p36.31), del(5)(q35), del(13)(q14.3), del(16)(q22.1) and del(19)(p13.2). From these, the cryptic deletion, del(5)(q35), was exclusively identified in about 25% of TLX3 rearranged T-ALL cases. In addition, 19 other genetic lesions were detected once in TLX3 rearranged T-ALL cases, including a cryptic WT1 deletion and a deletion covering the FBXW7 gene, an U3-ubiquitin ligase that mediates the degradation of NOTCH1, MYC, JUN and CyclinE. This study provides a genome-wide overview of copy number changes in TLX3 rearranged T-ALL and offers great new challenges for the identification of new target genes that may play a role in the pathogenesis of T-ALL.
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PMID:Cooperative genetic defects in TLX3 rearranged pediatric T-ALL. 1818 24

The objective of this study was to examine the effect of sodium bicarbonate (NaHCO3-) ingestion on performance and perceptual responses in a laboratory-simulated bicycle motocross (BMX) qualification series. Nine elite BMX riders volunteered to participate in this study. After familiarization, subjects undertook two trials involving repeated sprints (3 x Wingate tests [WTs] separated by 30 minutes of recovery; WT1, WT2, WT3). Ninety minutes before each trial, subjects ingested either NaHCO3- or placebo in a counterbalanced, randomly assigned, double-blind manner. Each trial was separated by 4 days. Performance variables of peak power, mean power, time to peak power, and fatigue index were calculated for each sprint. Ratings of perceived exertion were obtained after each sprint, and ratings of perceived readiness were obtained before each sprint. No significant differences were observed in performance variables between successive sprints or between trials. For the NaHCO3- trial, peak blood lactate during recovery was greater after WT2 (p < 0.05) and tended to be greater after WT3 (p = 0.07), and ratings of perceived exertion were not influenced. However, improved ratings of perceived readiness were observed before WT2 and WT3 (p < 0.05). In conclusion, NaHCO3- ingestion had no effect on performance and RPE during a series of three WT simulating a BMX qualification series, possibly because of the short duration of each effort and the long recovery time used between the three WTs. On the contrary, NaHCO3- ingestion improved perceived readiness before each WT.
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PMID:Effects of sodium bicarbonate ingestion on performance and perceptual responses in a laboratory-simulated BMX cycling qualification series. 1871 19


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