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Homo sapiens
24 Downloadable Samples
Illumina HiSeq 2000, NextSeq 500
Description
FAM46C is one of the most frequently mutated genes in multiple myeloma (MM) and encodes a protein of unknown function. Using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active cytoplasmic non-canonical poly(A) polymerase, which enhances mRNA stability and gene expression. Moreover, we also found that the reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induced cell death. This is, to our knowledge, the first report that directly associates cytoplasmic poly(A) polymerase with carcinogenesis. Furthermore, our data suggest that the human genome encodes at least eleven non-canonical poly(A) polymerases with four FAM46 family members. Since FAM46 proteins are differentially expressed during development, these proteins may positively regulate transcript stability and translational rate in a tissue-specific manner. Overall design: The H929 and SKMM1 MM cells were transduced with lentiviruses carrying FAM46CWTGFP (WT) or FAM46CD90A,D92AGFP (catalitic mutant). 72h after transgene delivery total RNA was extracted and RNA-seq libraries were prepared.
Publication Title
The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 10 Downloadable Samples
Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Biologic characterization of SB-559457 (SB), a non-peptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity towards human leukemia cells. Anti-proliferative effects followed by significant, non-apoptotic, cell death within 72 hours occurred in 24/26 AML, 0/6 ALL, and 3/6 CML patient samples exposed to SB, but not recombinant human thrombopoietin (rhTpo), in liquid suspension culture. Further investigation revealed increased phosphorylation of p70S6/S6 kinases in SB, but not in rhTpo, treated cells. Expression profiling of cells exposed to SB vs rhTpo revealed statistically significant, ~2-fold changes in GAPDH and REDD1 gene expression, confirmed by QRT-PCR. These genes, induced in energy or hypoxia stressed cells, have been implicated in cell death pathways, and may provide important clues to the mechanism of SB induced, leukemic cell death. These results suggest that nonpeptidyl, hydrazone class Mpl agonists may be clinically useful anti-leukemic agents by virtue of their combined thrombopoietic and anti-leukemic effects.
Publication Title
A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells.
Sample Metadata Fields
Specimen part, Disease, Treatment
View Samples- Homo sapiens
- 32 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Epstein Barr virus (EBV) nuclear antigen 3C (EBNA3C) is an essential transcription factor for initiating and maintaining human B lymphocyte transformation to lymphoblastoid cell lines (LCLs). To comprehensively identify EBNA3C regulated cell genes in LCLs, oligonucleotide arrays were used to compare RNA abundances in 3 different LCLs transformed by an EBV that conditionally expresses EBNA3C. Cell RNA levels were assessed in actively growing LCLs, under non-permissive or permissive conditions or under non-permissive conditions after transcomplementation with wild type EBNA3C. A two-way ANOVA model with covariates including the 3 different clone effects and the 3 EBNA3C expression levels, identified 550 EBNA3C regulated genes, with False Discovery Rate <0.01 and >1.5 fold change. A seeded Bayesian network analysis of the 80 most significantly EBNA3C regulated genes that changed >1.5 fold, positioned RAC1, LYN and TNF upstream of other EBNA3C regulated genes. Further, Gene Set Enrichment Assay (GSEA) identified EBNA3C regulated genes to be enriched for MAP kinase signaling, cytokine-cytokine receptor interactions, JAK-STAT signaling, and cell adhesion molecule effects, implicating these pathways in LCL growth or survival. Moreover, 106 EBNA3C regulated genes could be placed in protein interaction networks. Since CXCL12 and CXCR4 signaling are implicated in LCL growth and were EBNA3C up-regulated, up-regulation of CXCL12 was validated by qRT-PCR and effects on induced LCL migration were confirmed. EBNA3C regulated genes significantly overlapped with EBNA2 and EBNA3A regulated genes, consistent with a central role for RBP/CSL in these effects.
Publication Title
Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 Transformation Effector Site 2 (TES2)/C-Terminal Activation Region 2 (CTAR2) activates NF-kappaB, p38, JNK, ERK and IRF7 pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK 293 cells. Using a False Discovery Rate (FDR) of < 0.001 after correction for multiple hypotheses, LMP1 TES2 caused > 2-fold changes in 1916 mRNAs; 1479 RNAs were up-regulated and 437 down-regulated. In contrast to TNFalpha stimulation, which transiently up-regulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as IkappaBalpha and A20. LMP1 TES2 regulated RNAs encode many NF-kappaB signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene Set Enrichment Analyses found LMP1 TES2 up-regulated genes to be significantly enriched for Pathways in Cancer, B-and T-cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and IkappaBalpha super-repressor co-expression decreased LMP1 TES2 RNA effects to only 5 RNAs with FDR<0.001 and >2 fold change. Thus, canonical NF-kappaB activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated.
Publication Title
Canonical NF-kappaB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
Activators of innate immunity may have potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin (IL)-22, which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection, and thus holds promise as a broad-spectrum antiviral agent. Overall design: Total mRNA from intestinal epithelial cells of Rag1-/- mice treated with PBS, IL-18, IL-22 or IL-22/IL-18 was assayed for RNA sequencing.
Publication Title
Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18.
Sample Metadata Fields
No sample metadata fields
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GSE68269- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The goal of this project is to identify genes preferentially expressed in inflammatory macrophages as compared with control macrophages.
Publication Title
Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage.
Sample Metadata Fields
Specimen part, Treatment
View Samples