Demethyl fructiculin A is a diterpenoid quinone component of the exudates from Salvia corrugata (SCO-1) leafes. SCO-1 was recently reported to induce anoikis in mammalian cell lines via a molecular mechanism involving the presence of the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36, showed that SCO-1 was able to induce apoptosis also via alternate pathways. To contribute to a better characterization of the molecular mechanisms underlining the cytotoxic activity of SCO-1, we decided to pursue an unbiased pharmacogenomic approach by generating the gene expression profile of GBM TICs subjected to the administration of SCO-1 and comparing it with that of control cells exposed to the solvent. With this strategy we hypothesized to highlight those pathways and biological processes unlashed by SCO-1.
Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.
Time
View SamplesDiamond-Blackfan Anemia (DBA) is a rare inherited red cell hypoplasia characterized by a defect in the maturation of erythroid progenitors and is in some cases associated to malformations. Patients have an increased risk of solid tumors. Mutations have been found in several ribosomal protein (RP) genes. Studies in hematopoietic progenitors from patients show that the haploinsufficiency of an RP impairs rRNA processing and ribosome biogenesis. DBA lymphocytes and fibroblasts show reduced protein synthesis, and the latter display abnormal rRNA processing and impaired proliferation.
Fibroblasts from patients with Diamond-Blackfan anaemia show abnormal expression of genes involved in protein synthesis, amino acid metabolism and cancer.
Sex, Disease, Disease stage
View SamplesHeat stress is one of the most prominent and deleterious environmental threads affecting plant growth and development. Upon high temperatures, plants launch specialized gene expression programs that promote stress protection and survival. These programs involve global and specific changes at the transcriptional and translational levels. However the coordination of these processes and their specific role in the establishment of the heat stress response is not fully elucidated.
Analysis of genome-wide changes in the translatome of Arabidopsis seedlings subjected to heat stress.
Specimen part
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The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression.
Specimen part, Cell line
View SamplesAberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation.
The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression.
Specimen part, Cell line
View SamplesAberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation.
The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression.
Specimen part, Cell line
View SamplesWe show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin- CD34-) hematopoietic stem cells (HSCs) from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular caryotyping and quantitative analysis of BCR/ABL transcript demonstrated that about one third of CD34- was leukemic. CML CD34- cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures and cytokines induced CD34 expression on some HSCs, cell cycling, acquisition of clonogenic activity and increased expression of BCR/ABL transcript. CML CD34- cells showed an engraftment rate in immunodeficient mice similar to that of CD34+ cells. Gene expression profiling revealed the down-regulation of cell cycle arrest genes together with genes involved in antigen presentation and processing, while the expression of angiogenic factors was strongly up-regulated when compared to normal counterparts. Flow cytometry analysis confirmed the significant down-regulation of HLA class I and II molecules in CML CD34-cells. Increasing doses of imatinib mesilate (IM) did not affect fusion transcript levels, BCR-ABL kinase activity and the clonogenic efficiency of CML CD34- cells as compared to leukemic CD34+cells.
Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib.
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View SamplesBACKGROUND: The daily gene expression oscillations that underlie mammalian circadian rhythms show striking differences between tissues and involve post-transcriptional regulation. Both aspects remain poorly understood. We have used ribosome profiling to explore the contribution of translation efficiency to temporal gene expression in kidney, and contrasted our findings with liver data available from the same mice. RESULTS: Rhythmic translation of constantly abundant mRNAs affects largely nonoverlapping transcript sets with distinct phase clustering in the two organs. Moreover, tissue differences in translation efficiency modulate the timing and amount of protein biosynthesis from rhythmic mRNAs, consistent with organ-specificity in clock output gene repertoires and rhythmicity parameters. Our comprehensive datasets provided insights into translational control beyond temporal regulation. Between tissues, many transcripts show differences in translation efficiency, which are, however, of markedly smaller scale than mRNA abundance differences. Tissue-specific changes in translation efficiency are associated with specific transcript features and, intriguingly, globally counteracted and compensated transcript abundance variations, leading to higher similarity at the level of protein biosynthesis between both tissues. CONCLUSIONS: We show that tissue-specificity in rhythmic gene expression extends to the translatome and contributes to define the identities, the phases and the expression levels of rhythmic protein biosynthesis. Moreover, translational compensation of transcript abundance divergence leads to overall higher similarity at the level of protein production across organs. The unique resources provided through our study will serve to address fundamental questions of post-transcriptional control and differential gene expression in vivo. Overall design: A total of 48 mice were entrained under 12hours light:dark conditions for 2 weeks and also collected under 12hours light:dark. Mice were sacrificed every two hours during the 24 hours daily cycle. Two replicates per time point, each replicate is a pool of livers or kidneys from 2 animals.
Translational contributions to tissue specificity in rhythmic and constitutive gene expression.
Sex, Cell line, Subject, Time
View SamplesThe role of androgen in breast cancer development is not fully understood although androgen receptors (AR) have been identified in breast cancer clinical samples and cell lines. However the whole spectra of androgen actions cannot be accounted to the classic AR mode of action and the possible existence of a cell surface AR has been suggested. Indeed androgens like all steroids have been reported to trigger membrane initiated signaling activity and exert specific actions. Androgens acting on the membrane can rapidly activate kinase signaling pathways and ultimately could affect gene expression. However, the molecular nature of membrane androgen binding sites represents another major persisting question. In the present study, we investigated early transcriptional effects of testosterone and the impermeable testosterone-BSA conjugate, in two breast cancer cell lines, in an attempt to decipher specific genes modified in each case, providing evidences about specific membrane initiating actions. Our data indicate that the two agents tested affect the expression of several genes. A group of genes were commonly affected while others were uniquely modified by each agent. In MDA-MB-231 cells, that are AR negative, the majority of genes affected by testosterone were also affected by testosterone-BSA indicating a membrane action. Subsequent analysis revealed that the two agents trigger different molecular pathways and cellular/molecular functions, suggestive of a molecular heterogeneity of membrane and intracellular AR. In addition, the phenotypic interactions of membrane-acting androgen with growth factor were verified at the transcriptomic level. Finally an interesting interplay between membrane-acting androgen with inflammation-related molecules, with potential clinical implications was revealed.
Conjugated and non-conjugated androgens differentially modulate specific early gene transcription in breast cancer in a cell-specific manner.
Specimen part, Cell line
View Samples-cell identity is determined by tightly regulated transcriptional networks that are modulated by extracellular cues, thereby ensuring -cell adaptation to the organisms insulin demands. We have observed in pancreatic islets that stimulatory glucose concentrations induced a gene profile that was similar to that of freshly isolated islets, indicating that glucose-elicited cues are involved in maintaining -cell identity. Low glucose induces the expression of ubiquitous genes involved in stress responses, nutrient sensing, and organelle biogenesis. By contrast, stimulatory glucose concentrations activate genes with a more restricted expression pattern (- and neuronal- cell identity). Consistently, glucose-induced genes are globally reduced in islets deficient with Hnf1a (MODY3), characterized by a deficient glucose metabolism. Of interest, a cell cycle gene module was the most enriched among the variable genes between intermediate and stimulatory glucose concentrations. Glucose regulation of the islet transcriptome was unexpectedly broadly maintained in islets from aged mice. However, the cell cycle gene module is selectively lost in old islets and the glucose activation of this module is not recovered even in the absence of the cell cycle inhibitor p16.
Glucose regulation of a cell cycle gene module is selectively lost in mouse pancreatic islets during ageing.
Specimen part
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