Gene expression profile of acute myeloid leukemia.
Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia.
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View SamplesIxr1 is a transcriptional factor from Saccharomyces cerevisae with high affinity to cisplatin-DNA adducts through their two HMG-box DNA binding domains. Its transcriptional regulation is essential in the cytotoxicity caused by cisplatin, although the molecular mechanisms supporting this function are not understood. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin which are dependent or independent of the Ixr1 function.
Ixr1 Regulates Ribosomal Gene Transcription and Yeast Response to Cisplatin.
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View SamplesRecent studies suggest that telomerase promotes cell growth by mechanisms that extend beyond the rescue of critically short telomeres. The in vitro model of mTert overexpressing MEFs recapitulates fundamental aspects of the growth-promoting effects of mTert in vivo. First, in Terc-proficient cells, mTert overexpression favors escape from replicative senescence and enhances anchorage-independent growth in response to oncogenic stress, which fits well with previous data showing that mTert overexpression promotes tumor formation. Second, in Terc-deficient cells, retroviral transduction with mTert results in a delayed onset of immortalization and impairs colony formation in response to oncogenic stress, which is in agreement with the inhibitory effect of mTert overexpression on tumorigenesis in a Terc null mouse background. To unravel the molecular targets of telomerase that impact on cell growth, we compared the transcriptome of MEFs, before and after mTert introduction. We found that ectopic expression of mTert was associated with detectable gene expression changes (greater than 1.5-fold; validated by qRT-PCR) of 26 transcripts. Analysis of the observed transcriptional changes indicates that ectopic expression of mTert suppresses in a coordinated manner functionally related genes with overlapping roles in growth arrest, resistance to transformation, and apoptosis. We show that the majority of the telomerase target genes are growth-inhibitory, transforming growth factor-beta (TGF-beta) -inducible genes and provide functional evidence for the potential of telomerase to abrogate TGF-beta -mediated growth inhibition. Thus, in line with the current view that the diversity of TGF-beta responses is not so much a consequence of the use of different signaling pathways but caused by different ways of reading the output from the same basic pathway, we propose that the telomerase status of a cell creates a gene expression pattern that determines how cells read growth inhibitory signals, among them signals propagated through the TGF-beta pathway.
Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-beta signaling.
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View SamplesIn this study we analyzed the behavior of bone marrow MSC (BM-MSC) from MPN patients with the mutation in JAK2V617F. We initially characterized the biological function and gene expression profile changes in BM-MSC from MPN patients when compared to BM-MSC of healthy donors (HD). Then, we established co-cultures between MSC cell lines (HTERT and HS5) and the UKE-1 MPN cell line, and performed RT-PCR to study if the leukemic cells were able to modify the genes related to hematopoietic support.
Mesenchymal stromal cells (MSC) from JAK2+ myeloproliferative neoplasms differ from normal MSC and contribute to the maintenance of neoplastic hematopoiesis.
Specimen part, Disease stage, Subject
View SamplesDeregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.
Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.
Specimen part
View SamplesAtrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts.
Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk.
Specimen part
View SamplesSky1 is a Saccharomyces cerevisiae rich serine-arginine (SR) protein-specific kinase and its enzymatic activity is essential in the cytotoxicity caused by cisplatin, although the molecular mechanisms supporting this function are not understood. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin which are dependent or independent of the Sky1 function.
Sky1 regulates the expression of sulfur metabolism genes in response to cisplatin.
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View SamplesAnalysis of primary bovine aortic endothelial cells treated for 24 hours with TGF-beta 1 5 ng/ml. TGF-beta 1 has been shown to induce endothelial-to-mesenchymal transition (EndoMT) and to be implicated in differentiation of endothelial cells into smooth muscle-like cells as occurred in vascular neointimal formation.
LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
A genome-wide function of THSC/TREX-2 at active genes prevents transcription-replication collisions.
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View SamplesTranscription is a major obstacle for replication fork progression and a cause of genome instability. Such instability increases in mutants with a suboptimal assembly of the nascent messenger ribonucleo-protein particle (mRNP), as THO/TREX and the NPC-associated THSC/TREX-2 complex.
A genome-wide function of THSC/TREX-2 at active genes prevents transcription-replication collisions.
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