Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is are often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), a well known human respiratory carcinogen that induces a wide spectrum of DNA damage, in the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate. Notably, PTP inhibition abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after PTP inhibition was predominantly due to a bypass of cell cycle arrest and was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by PTP inhibition, was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in the Cr(VI)-induced expression of cell cycle promoting genes. Importantly, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability, via bypass of cell cycle checkpoints.
Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: enhanced survival and mutagenesis.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
Specimen part
View SamplesProstate cancer (PCa) tends to be more aggressive and lethal in African Americans (AA) compared to European Americans (EA). To further understand the biological factors accounting for the PCa disparities observed in AA and EA patients, we performed gene profiling using Affymetrix human exon 1.0 ST arrays to identify the differentially expressed genes beween AA cancer and patient matched normal tissues.
Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
Specimen part
View SamplesProstate cancer (PCa) tends to be more aggressive and lethal in African Americans (AA) compared to European Americans (EA). To further understand the biological factors accounting for the PCa disparities observed in AA and EA patients, we performed gene profiling analysis using Affymetrix human exon 1.0 ST arrays to identify the differentially expressed genes in AA and EA patients.
Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
Specimen part
View SamplesProstate cancer (PCa) tends to be more aggressive and lethal in African Americans (AA) compared to European Americans (EA). To further understand the biological factors accounting for the PCa disparities observed in AA and EA patients, we performed gene profiling analysis using Affymetrix human exon 1.0 ST arrays to identify the differentially expressed genes in EA PCa vs. EA normal.
Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
Specimen part
View Sampleseffect of overexpression of GATA-6 in P19 CL6 induced cells
Wnt2 is a direct downstream target of GATA6 during early cardiogenesis.
Cell line
View SamplesThe goal of this study is to perform RNAseq in different sub-types of the zebrafish embryonic dorsal aorta (DA) at 28-30 hpf using TgBAC(runx1P2:Citrine);Tg(kdrl:mCherry) double-transgenic zebrafish embryos. A min. of 3000 cells per population were collected via FACS. RNA was isolated with the RNeasy Plus Micro Kit (QIAGEN, Cat No. 74034). High quality RNA (RIN > 8.0) was sent for RNAseq to the Wellcome Trust Centre for Human Genetics (WTCHG). 2.2 ng of total RNA was used to generate SMARTer libraries for low-input RNA. Sequencing was performed on an Illumina HiSeq4000 machine with a 75 bp paired end protocol. Sequenced reads were checked for base qualities, trimmed where 20% of the bases were below quality score 20, and filtered to exclude adapters using Trimmomatic (Version 0.32). Sequences were aligned to the Zebrafish Genome Zv10 with STAR with default parameters. Aligned read features were counted using Subread tool: featureCounts method (version 1.4.5-p1). To determine number of mapped reads we used the trimmed data. The alignment has been performed using STAR with default parameters. The number of mapped reads (QC-passed reads count) has been obtain using Samtools mapping statistics (flagstat tool). Overall design: Analysis of 5 different cell types; DN (double negative), SP-kdrl (single positive), DP-R1lo (double positive runx1 low expression), DP-R1med (runx1 medium expressionand) and DP-R1hi (runx1 high expression) in non-injected (Wt) TgBAC(runx1P2:Citrine);Tg(kdrl:mCherry) double-transgenic zebrafish embryos. Analysis was also done of the DN and DP-R1hi populations in runx1-morpholino (MO) injected embryos.
Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium.
Specimen part, Subject
View SamplesThe innate immune response is primarily mediated by the Toll-like receptors functioning through the Myd88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of genes activated during the innate immune response using a novel approach to analyze time course gene expression profiles of activated immune cells in combination with a large gene regulatory and protein-protein interaction network. We classified the immune response into three consecutive time-dependent stages and identified the most probable paths between genes showing a significant change in expression at each stage. The resultant network contained several novel and known regulators of the innate immune response, many of which did not show any observable change in expression at the sampled time points. The response network shows the dominance of genes from specific functional classes during different stages of the immune response. It also suggests a role for the protein phosphatase 2a catalytic subunit a in the regulation of the immunoproteasome during the late phase of the response. In order to clarify the differences between the Myd88-dependent and TRIF-dependent pathways in the innate immune response, time course gene expression profiles from Myd88-knockout and TRIF-knockout dendritic cells were analyzed. Their response networks suggest the dominance of the MyD88 dependent pathway in the innate immune response, and an association of the circadian regulators and immunoproteasomal degradation with the TRIF-dependent pathway. The response network presented here provides the most probable associations between genes expressed in the early and the late phases of the immune response, while taking into account the intermediate regulators. We propose that the method described here can also be used in the identification of time-dependent gene subnetworks in other biological systems.
Discovery of Intermediary Genes between Pathways Using Sparse Regression.
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View SamplesCell lines derived from tumor tissues have been used as a valuable system tostudy gene regulation and cancer development. Comprehensive characterization ofthe genetic background of cell lines could provide clues on novel genes responsiblefor carcinogenesis and help in choosing cell lines for particular studies. Here, we havecarried out whole exome and RNA sequencing of commonly used glioblastoma (GBM)cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotidevariations (SNVs), indels, differential gene expression, gene fusions and RNA editingevents. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) werepotentially cancer-specific. The cell lines showed frequent SNVs and indels in someof the genes that are known to be altered in GBM- EGFR, TP53, PTEN, SPTA1 andNF1. Chromatin modifying genes- ATRX, MLL3, MLL4, SETD2 and SRCAP also showedalterations. While no cell line carried IDH1 mutations, five cell lines showed hTERTpromoter activating mutations with a concomitant increase in hTERT transcript levels.Five significant gene fusions were found of which NUP93-CYB5B was validated. Anaverage of 18,949 RNA editing events was also obtained. Thus we have generated acomprehensive catalogue of genetic alterations for six GBM cell lines.
Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing.
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View SamplesBackground
Global transcriptional response of Saccharomyces cerevisiae to the deletion of SDH3.
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