The effect of CLA on gene expression in Caco-2 cells
Conjugated linoleic acid alters global gene expression in human intestinal-like Caco-2 cells in an isomer-specific manner.
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View SamplesThere is emerging evidence that, beyond their cholesterol lowering properties, statins exhibit important antileukemic effects in vitro and in vivo, but the precise mechanisms by which they generate such responses remain to be determined. We have previously shown that statins promote differentiation of acute promyelocytic leukemia (APL) cells and enhance generation of all-trans-retinoic acid (ATRA)-dependent antileukemic responses. We now provide evidence that statin-dependent leukemic cell differentiation requires engagement and activation of the JNK kinase pathway. In addition, in experiments to define the molecular targets and mediators of statin-induced differentiation we found a remarkable effect of statins on ATRA-dependent gene transcription, evidenced by the selective induction of over 400 genes by the combination of atorvastatin and ATRA. Altogether, our studies identify novel statin molecular targets linked to differentiation, establish that statins modulate ATRA-dependent transcription, and suggest that combined use of statins with retinoids may provide a novel approach to enhance antileukemic responses in APL and possibly other leukemias.
Regulation of leukemic cell differentiation and retinoid-induced gene expression by statins.
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View SamplesPRDM proteins belong to the SET domain protein family, which is involved in the regulation of gene expression. Although few PRDM members possess histone methyltransferase activity, the molecular mechanisms by which the other members exert transcriptional regulation remain to be delineated. In this study, we find that Prdm5 is highly expressed in mouse embryonic stem (mES) cells and exploit this cellular system to characterize molecular functions of Prdm5. By combining proteomics and next-generation sequencing technologies, we identify Prdm5 interaction partners and genomic occupancy. We demonstrate that although Prdm5 is dispensable for mES cell maintenance, it directly targets genomic regions involved in early embryonic development and affects the expression of a subset of developmental regulators during cell differentiation. Importantly, Prdm5 interacts with Ctcf, cohesin, and TFIIIC and cooccupies genomic loci. In summary, our data indicate how Prdm5 modulates transcription by interacting with factors involved in genome organization in mouse embryonic stem cells. Overall design: For each condition (ATRA-induced differentiation model and LIF cytokine deprivation) three replicate are available for both Prdm5 wt mES cells and Prdm5 KO mES cells, for a total of 12 samples
Genomic and proteomic analyses of Prdm5 reveal interactions with insulator binding proteins in embryonic stem cells.
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View SamplesThe homeobox containing gene Arx is expressed during ventral telencephalon development and it is required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose syntoms are compatible with a loss of cortical interneurons and altered basal ganglia related-activities in humans. Herein, we reported the identification by global expression profiling of a group of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Following analysis revealed the striking ectopic expression in the ganglionic eminences of a number of genes normally not, or only marginally, expressed in the ventral telencephalon. Among them, we functionally analyzed Ebf3, whose ectopic expression in ventral telencephalon is preventingneuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissue might marginally rescue tangential cell movements. Together, these data provide an initial analysis of the molecular pathways regulated by Arx and how their networking might regulate those specific cellular processes during telencephalon development strongly altered by loss of Arx.
Arx acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity.
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View Samplesp63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC syndrome, ADULT syndrome and AEC syndrome . The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. We report a study on the TAp63a isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63a wt, DeltaNp63 alpha or the TAp63 alpha-Q540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63a and causes misregulation of genes involved in the control of cell growth and epidermal differentiation.
The Hay Wells syndrome-derived TAp63alphaQ540L mutant has impaired transcriptional and cell growth regulatory activity.
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View SamplesIn the past few years, mammary cancer initiating cells (CICs) have been identified in mouse and human as a subpopulation of tumor cells that selectively posses tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of non-tumorigenic cancer cells progeny through differentiation. They could also be responsible for tumor progression, metastasis, resistance to therapy and recurrence. Thus, the understanding of the pathways regulating CIC self-renewal, differentiation and tumorigenicity represents an important task in the development of effective anticancer therapies.
The noninflammatory role of high mobility group box 1/Toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells.
Specimen part, Cell line
View SamplesMicroarrays have been widely used for the analysis of gene expression and several commercial platforms are available. The combined use of multiple platforms can overcome the inherent biases of each approach, and may represent an alternative that is complementary to RT-PCR for identification of the more robust changes in gene expression profiles.
Cross platform microarray analysis for robust identification of differentially expressed genes.
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View SamplesEndometriosis is a complex pathological condition in which multiple components are involved in the disease development and clinical outcome. Endometriosis is mainly an inflammatory codition estrogen-dependent, with unknown pathogenesis, that is characterized by dissemination of edometrium tissue in ectopic position (ovary or pelvic peritoneum). Two main theories rise the pathologic onset: the presence of retrograde menstruation and celomic metaplasia in the pelvic peritoneum, that can occur for development defects. Endometriosis is related not only to genetic or immunological changes and to environmental pollution factors, as the endocrine interferents. The disease phenotype results from multiple events (genetics and enviromental), thus it is difficult to find a single gene as causative while is more probable that a gene network/s might involved in the onset and mantainement of the disease state. The peculiarity of endometriosis rely on the tissue speificity manteinance in the ectopic position, where it responds to the hormone stimuli as the tissue in the eutopic position.
Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects.
Specimen part, Disease, Disease stage, Subject
View SamplesTreatment with Aurora inhibitors has been shown to induce diverse biological responses in different tumor cell lines, in part depending on their p53 status. To characterize at the transcriptional level the effects of Danusertib we analyzed by microarray different tumor cell lines, with WT or mutant p53 status, that showed differential cell cycle response upon drug treatment.
Transcriptional analysis of the Aurora inhibitor Danusertib leading to biomarker identification in TP53 wild type cells.
Specimen part, Cell line
View SamplesAdvanced ovarian cancers are initially responsive to chemotherapy with platinum drugs but develop drug resistance in most cases. We showed recently that hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and that this effect is mediated by the p38 mitogen-activated protein kinase. In this work, we integrated genome-wide expression profiling, in silico data survey, and functional assays to identify transcripts regulated in SK-OV-3 ovarian cancer cells made more responsive to CDDP by HGF. Using oligonucleotide microarrays, we found that HGF pretreatment changes the transcriptional response to CDDP. Quantitative reverse transcription-PCR not only validated all the 15 most differentially expressed genes but also confirmed that they were primarily modulated by the combined treatment with HGF and CDDP and reversed by suppressing p38 mitogen-activated protein kinase activity. Among the differentially expressed genes, we focused functional analysis on two regulatory subunits of the protein phosphatase 2A, which were down-modulated by HGF plus CDDP. Decrease of each subunit by RNA interference made ovarian cancer cells more responsive to CDDP, mimicking the effect of HGF. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or revert chemotherapy resistance.
Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin.
Cell line
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