Post-translational regulation of the MYC Transcription Factor (TF), including its phosphorylation and ubiquitination, plays an important role in determining cell proliferation and apoptosis and has been implicated in tumorigenesis. Using a computational systems biology approach, followed by biochemical and functional validation, we have characterized the role of the STK38 kinase, an NDR family serine-threonine kinase, as a key modulator of MYC transcriptional activity in human B cells, affecting MYC protein stability in a signal-dependent fashion. Specifically, we show that in human B lymphoma ST486 cells STK38 is a key mediator of BCR pathway signaling, affecting MYC protein turnover and its phosphorylation at Ser62 in kinase-activity-dependent manner. STK38 inactivation abrogates apoptosis following BCR activation while its silencing mediates MYC protein degradation via canonical proteolytic pathways. This suggests that STK38 could provide an effective therapeutic target in MYC-dependent malignancies.
STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.
Cell line, Time
View SamplesWe examined if pediatric AMLs rank-ordered according to C/EBP expression showed the activation of similar pathways. AML samples were dichotomized into groups including the upper quartile (Q1) and the lower three quartiles (Q2-4) according to their C/EBP expression values. Moreover, AML samples were associated to French-American-British (FAB) classification.
CREB engages C/EBPδ to initiate leukemogenesis.
Specimen part, Disease
View SamplesTo examine the role of CREB overexpression in hematopoiesis, we created a model of leukemia in zebrafish by overexpressing the human CREB in the myeloid hematopoietic lineage. Whole transcriptome analysis of kidney-marrow revealed 171 genes differently expressed between CREB- and control-zebrafish (five per group). Interestingly, the integration of this signature with human deposited data revealed that this tumor resembled a human AML at transcriptome level.
CREB engages C/EBPδ to initiate leukemogenesis.
Specimen part
View SamplesDemethyl 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 SamplesWe had evidence that TRIM5 regulates signal transduction, specifically NFkB and MAPK pathways. To test the role of endogenous TRIM5 we used the myelomonocytic leukemia cell line THP1. These cells were transduced with a lentiviral vector that delivers a miRNA engineered to knockdown TRIM5. The vector also encoded a puromycin-resistance cassette and transduced cells were selected in poold with puromycin. As a control, cells were transduced with a vector targeting luciferase instead of TRIM5.
TRIM5 is an innate immune sensor for the retrovirus capsid lattice.
Specimen part, Cell line
View SamplesWe examined if the minimal residual disease (MRD) and the Allelic Ratio (AR) of FLT3 internal tandem duplication (ITD) mutated patients may be prognostic factors. We correlated these parameters both with event free survival (EFS), with incidence of relapse and with gene expression profile (GEP). GEP showed that patients with high-ITD-AR or persistent MRD had different expression profiles. Results indicated that the ITD-AR levels and the MRD after I induction course are associated with transcriptional oncogenic profiles, which highlight differences in epigenetic control that may explain the variability in outcome among FLT3-ITD patients
Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.
Specimen part, Disease
View SamplesWe have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. In order to identify underlying commonalities in gene transcription associated with the phenotype, we compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (acini), the malignant T4-2 cells that form large tumor-like clusters, and the phenotypically reverted T4-2 cells that polarize as a result of correction of the microenvironmental signaling.
Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context.
Specimen part, Treatment
View SamplesNitric oxide being a versatile molecule inside biological systems, from being both a cell signaling molecule to a potent stress agent, has significant effect in the transcriptional response in fission yeast.
Global transcriptomic profiling of Schizosaccharomyces pombe in response to nitrosative stress.
No sample metadata fields
View SamplesThis study was designed to provide a genome-wide analysis of the effects of luteinizing hormone (LH) ablation/replacement versus steroid ablation/replacement on gene expression in the developed corpus luteum (CL) in primates during the menstrual cycle. Naturally cycling, female rhesus monkeys were left untreated (Control; n = 4) or received one of the following treatments for three days beginning on Day 9 of the luteal phase: daily injection of the gonadotropin-releasing hormone (GnRH) antagonist (Antide; n = 5), Antide + recombinant human LH (A+LH; n = 4), Antide + LH + the 3b-HSD antagonist Trilostane (A+LH+TRL; n = 4), and Antide + LH + TRL + progesterone replacement with a synthetic progestin R5020 (A+LH+TRL+ R5020; n = 5). On Day 12 of the luteal phase, CL were removed and samples of RNA from individual CL were fluorescently labeled and hybridized to Affymetrix rhesus macaque total genome microarrays. The greatest number of altered transcripts was associated with the ablation/replacement of LH, while ablation/replacement of progestin affected fewer transcripts. Replacement of LH during Antide treatment restored expression of most transcripts to control levels. Real-time PCR validation of a subset of transcripts revealed that most expression patterns were similar between microarray and real-time PCR. Analysis of protein levels were subsequently determined for 2 of the transcripts differentially expressed by real-time PCR. This is the first genome-wide analysis of LH and steroid regulation of gene transcription in the developed primate CL. Further analysis of novel transcripts identified in this data set can clarify the relative role for LH and steroids in CL maintenance and luteolysis.
The effects of luteinizing hormone ablation/replacement versus steroid ablation/replacement on gene expression in the primate corpus luteum.
No sample metadata fields
View SamplesTo obtain a genomic view of hepatocyte nuclear factor-4 (HNF-4) in the regulation of the inflammatory response, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokines in a model of knock-down HNF-4 HepG2 cells. The results indicate an extensive role for HNF-4 plays in the regulation of a large number of the liver-specific genes. Majority of genes (71%) affected by cytokine treatment are also affected by HNF-4 knock-down. This significant overlap suggests that HNF-4 may play a role in regulating the cytokine-induced inflammatory response.
Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α.
No sample metadata fields
View Samples