The antiapoptotic Bcl-2 family member Bfl-1 is upregulated in many human tumors in which NF-kB is implicated, and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kB induces transcription of bfl-1, and that the Bfl-1 protein is also regulated by the ubiquitin-proteasome. However little is known of the role that dysregulation of Bfl-1 turnover plays in cancer. We found that ubiquitination-resistant mutants of Bfl-1 display increased stability and greatly accelerate tumor formation in a mouse model of leukemia/lymphoma. Gene expression profiling revealed that tyrosine kinase Lck is highly upregulated and activated in these tumors compared to the parental cells, as were several genes in the RANK signaling pathway, and leads to activation of the IKK, Akt and Erk signaling pathways, which are key mediators in cancer. Tumor assays with cells coexpressing constitutively active Lck with Bfl-1, or with tumor-derived cells following shRNA-mediated Lck knockdown, unveiled functional cooperation between Bfl-1 and Lck in leukemia/lymphomagenesis. These data demonstrate that ubiquitination is a critical mechanism for regulating Bfl-1 function, and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose to cancer. Additionally since bfl-1 is upregulated in many human hematopoietic tumors, these data suggest that strategies to promote Bfl-1 ubiquitination may improve therapy in drug-resistant tumors.
Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma.
Disease
View SamplesMM1.S cells stably transduced with control or b-catenin shRNA were established. Total RNA was isolated from 5x 10^6 cells of each in triplicate.
Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression.
Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Transcriptomic response of murine liver to severe injury and hemorrhagic shock: a dual-platform microarray analysis.
Sex, Specimen part
View SamplesA dual platform microarray analysis was used to characterize the temporal transcriptomic response in the mouse liver following trauma and hemmorhagic shock
Transcriptomic response of murine liver to severe injury and hemorrhagic shock: a dual-platform microarray analysis.
Sex, Specimen part
View SamplesGene expression kinetics for BM-DM from C57BL/6 mouse stimulated with four different TLR ligands poly(I:C), R848, LPS, Pam3CSK4 either singly or in paired combination, for 1 hour, 4 hour, or 8 hour.
Systematic Investigation of Multi-TLR Sensing Identifies Regulators of Sustained Gene Activation in Macrophages.
Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Systematic Investigation of Multi-TLR Sensing Identifies Regulators of Sustained Gene Activation in Macrophages.
Treatment
View SamplesGene expression kinetics for BM-DM from C57BL/6 mice challenged by poly(I:C) , R848, poly(I:C)+R848 examined at 6 time points including 0.5, 1, 2, 4, 8, 12 h.
Systematic Investigation of Multi-TLR Sensing Identifies Regulators of Sustained Gene Activation in Macrophages.
Treatment
View SamplesMonastrol treatment of Leishmania donovani infected macrophages
A member of the Ras oncogene family, RAP1A, mediates antileishmanial activity of monastrol.
Specimen part, Disease, Treatment
View SamplesGene expression in HeLa cells was profiled using Affymetrix gene expression Human HG-U133_Plus_2 array. Transcript signal was mapped against the chromosome coordinates (probe-by-probe basis) using the HG-U133A_2 Annotations CSV file for hg18 build of the human genome provided by Affymetrix.
Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection.
Cell line
View SamplesThe mammalian innate immune system senses many bacterial stimuli through the toll-like receptor (TLR) family. Activation of the TLR4 receptor by bacterial lipopolysaccharide (LPS) is the most widely studied TLR pathway due to its central role in host responses to gram-negative bacterial infection and its contribution to endotoxemia and sepsis. Here we describe a genome-wide siRNA screen to identify genes regulating the human macrophage TNF- response to LPS. We include a secondary validation screen conducted with six independent siRNAs per gene to facilitate removal of off-target screen hits. We also provide microarray data from the same LPS-treated macrophage cells to facilitate downstream data analysis. These data provide a resource for analyzing gene function in the predominant pathway driving inflammatory cytokine expression in human macrophages.
Genome-wide siRNA screen of genes regulating the LPS-induced TNF-α response in human macrophages.
Specimen part, Cell line
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