Inhibition of phosphatidylinositol 3-kinase signaling in proliferating human T98G cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE10221 | GEO | 2008/01/24
SECONDARY ACCESSION(S): PRJNA108283
REPOSITORIES: GEO
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Project description:Gliomas are primary brain tumors with poor prognosis that exhibit frequent abnormalities in phosphatidylinositol 3-kinase (PI3 kinase) signaling. We investigated the molecular mechanism of action of the isoform-selective class I PI3 kinase and mTOR inhibitor PI-103 in human glioma cells. The potent inhibitory effects of PI-103 on the PI3 kinase pathway were quantified. PI-103 and the mTOR inhibitor rapamycin both inhibited ribosomal protein S6 phosphorylation but there were clear differences in the response of upstream components of the PI3 kinase pathway, such as phosphorylation of Thr308-AKT, that were inhibited by PI-103 but not rapamycin. Gene expression profiling identified altered expression of genes encoding regulators of the cell cycle and cholesterol metabolism, and genes modulated by insulin or IGF1 signaling, rapamycin treatment or nutrient starvation. PI-103 decreased expression of positive regulators of G1/S phase progression and increased expression of the negative cell cycle regulator p27kip1. A reversible PI-103-mediated G1 cell cycle arrest occurred without significant apoptosis, consistent with the altered gene expression detected. PI-103 induced vacuolation and processing of LC-3i to LC-3ii, which are features of an autophagic response. In contrast to PI-103, LY294002 and PI-387 induced apoptosis, indicative of likely off-target effects. PI-103 interacted synergistically or additively with cytotoxic agents used in the treatment of glioma, namely vincristine, BCNU and temozolomide. Compared to individual treatments, the combination of PI-103 with temozolomide significantly improved the response of U87MG human glioma xenografts. Our results support the therapeutic potential for PI3 kinase inhibitors with a PI-103-like profile as therapeutic agents for the treatment of glioma. Keywords: Key words: PI-103, glioma, PI3 kinase, mTOR, cell cycle, cytostasis
2009-04-21 | GSE12175 | GEO
Project description:Postnatal neural progenitors of the enteric nervous system are a potential source for future cell replacement therapies of developmental dysplasia like Hirschrpung’s disease. However, little is known about the molecular mechanisms driving the homeostasis and differentiation of this cell pool. In this work, we conducted Affymetrix gene chip experiments to identify differences in gene regulation between proliferation and early differentiation of enteric neural progenitors. We detected a total of 1333 regulated genes that were linked to different groups of cellular mechanisms involved in cell cycle, apoptosis, neural proliferation, and differentiation. As expected, we found a strong inhibition of cell cycle progression as well as an enhanced expression of neuronal and glial markers. We further found a marked inactivation of the canonical Wnt pathway during the beginning of cellular differentiation. Taken together, this data illustrated the various mechanisms taking place during the proliferation and early differentiation of enteric neural progenitor cells. We analyzed 2 groups with 3 samples each: 1 group consistent of cells proliferating für 11 days and 1 group of enterospheres proliferating for 9 days and differentiating for 2 days before RNA extraction
2015-05-13 | E-GEOD-68797 | biostudies-arrayexpress
Project description:Analysis of primary human CD4+ T cells stained with the proliferation tracker CFSE and stimulated with anti-CD3, anti-CD28, and PDL1 or PDL2 for 5 days. Cells were sorted at the end of stimulation based on number of proliferative doublings prior to RNA isolation. Results provide insight into the PD-1 response pathway in CD4+ T cells that are proliferating or non-proliferating following stimulation.
2021-10-20 | GSE159774 | GEO
Project description:Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL. To identify gene expression related to microenvironmental stimuli in B-cell Chronic Lymphocytic Leukemia (CLL) cells in vivo, expression profiles of CLL cells purified (>95%) from bone marrow (BM) and peripheral blood (PB) were compared. Paired BM and PB samples from 6 individuals were used for this analysis.
2011-07-25 | E-GEOD-30896 | biostudies-arrayexpress
Project description:Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib represent an effective strategy for treatment of chronic lymphocytic leukemia (CLL), although ~30% of patients eventually undergo disease progression. Here we investigated the long-term modulation of the CXCR4dim/CD5bright proliferative fraction (PF) and the CXCR4bright/CD5dim resting fraction (RF) in CLL samples, and their correlation with therapeutic outcome and emergence of ibrutinib resistance. Longitudinal tracking by flow cytometry revealed that PF, initially suppressed by ibrutinib, reappeared upon early disease progression suggesting that PF evaluation could represent a sensitive and specific marker of CLL progression upon ibrutinib treatment. Transcriptomic analyses of PF at progression revealed similar proliferation signatures between pre- and post-treatment PF, demonstrating the emergence upon progression of a newly proliferating cell population.
2024-04-02 | GSE249956 | GEO
Project description:Human adipose stem and progenitor cells (ASPCs) develop into heterogenous cultures of adipogenic and Structural Wnt-regulated Adipose Tissue resident (SWAT) cells upon induction of adipogenic differentiation. To investiagte the function of SWAT cells and compare them with proliferating ASPCs, we enriched the SWAT cells from the adipogenic cells using density gradient centriguation. The enriched SWAT cells were cultured for 24 hours in proliferation media or differentiation media for 24 hours. 4 density gradient centrifugations were performed, resulting in 4 technical replicates per media type. We included proliferating ASPCS (undifferentiated) as control. We then performed gene expression profiling analysis using data from RNA-Seq of 4 samples per condition (proliferating ASPCs, SWAT cells in proliferation media, SWAT cells in differentiation media)
2023-04-03 | GSE223588 | GEO
Project description:Purpose: Quiescence is a state or reversible cell cycle arrest. A previous study using microarrays (Coller et al., PMID: 16509772) revealed gene expression changes between quiescent and proliferating human dermal fibroblasts and defined a "quiescece program" of genes that change in abundance when fibroblasts were introduced into quiescence by one of three methods. The goal of this study is to perform high throughut RNA sequencing to determine global changes in gene expression between proliferating and quiescent human dermal fibroblasts. Methods: Three different biological replicates (corresponding to two fibroblast strains, 10-5 and 12-1) were collected in proliferating and contact--inhibited (quiescent) conditions. RNA extracted from these cells were used for library preparation. The libraries were sequenced on an Illumina HiSeq 2000 instrument. Results: Among the 19,673 genes monitored, 1,993 genes (10.1%) changed in expression two-fold or more, demonstrating widespread changes in gene expression with contact inhibition-induced quiescence. Fifty-two percent of these genes were upregulated in 7dCI compared with proliferating fibroblasts, and 48% were downregulated in 7dCI fibroblasts. Conclusions: There are widespread changes in gene expression as fibroblasts transition between proliferating and quiescent states.
2018-08-28 | GSE117444 | GEO
Project description:Inhibition of phosphatidylinositol 3-kinase signaling in proliferating human T98G cells
| PRJNA108283 | ENA
Project description:Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL.
2011-07-26 | GSE30896 | GEO
Project description:The budding yeast Saccharomyces cerevisiae alters its gene expression profile in response to a change in nutrient availability. The PHO-system is a well-studied case in the transcriptional regulation responding to nutritional changes in which a set of genes (PHO genes) is expressed to activate phosphate (Pi) metabolism for adaptation to Pi-starvation. Pi-starvation triggers an inhibition of Pho85 kinase, leading to migration of unphosphorylated Pho4 transcriptional activator into the nucleus enabling expression of PHO genes. When Pi is sufficient, the Pho85 kinase phosphorylates Pho4 thereby excluding it from the nucleus and resulting in repression (i.e., lack of transcription) of PHO genes. The Pho85 kinase has a role in various cellular functions other than regulation of the PHO system, in that Pho85 monitors whether environmental conditions are adequate for cell growth, and represses inadequate (untimely) responses in these cellular processes. In contrast, Pho4 appears to activate some genes involved in stress-response and is required for G1 arrest caused by DNA damage. These facts suggest the antagonistic function of these two players on a more general scale when yeast cells must cope with stress conditions. To explore general involvement of Pho4 in stress-response, we tried to identify Pho4-dependent genes by a genome-wide mapping of Pho4- and Rpo21-binding (Rpo21 being the largest subunit of RNA polymerase II) using a yeast tiling array. In the course of this study, we found Pi- and Pho4-regulated intragenic and antisense RNAs that could modulate the Pi-signal transduction pathway. Low-Pi signal is transmitted via certain inositol polyphosphate (IP) species (IP7) that are synthesized by Vip1 IP6 kinase. We have shown that Pho4 activates transcription of antisense and intragenic RNAs in the KCS1 locus to downregulate the Kcs1 activity, another IP6 kinase, by producing truncated Kcs1 protein via hybrid formation with the KCS1 mRNA and translation of the intragenic RNA, thereby enabling Vip1 to utilize more IP6 to synthesize IP7 functioning in low-Pi signaling. Since Kcs1 also can phosphorylate these IP7 species to synthesize IP8, reduction in the Kcs1 activity can ensure accumulation of the IP7 species, leading to further stimulation of low Pi-signaling, i.e., forming a positive feedback loop. We also report that genes apparently not involved in the PHO system are regulated by Pho4 either dependent upon or independently of the Pi conditions, and many of the latter genes are involved in stress-response. In S. cerevisiae, a large-scale cDNA analysis and mapping of RNA polymerase II binding using a high-resolution tiling array have identified a large number of antisense RNA species whose functions are yet to be clarified. Here we have shown that nutrient-regulated antisense and intragenic RNAs, as well as direct regulation of structural gene transcription, function in the response to nutrient availability. Our findings also imply that Pho4 is present in the nucleus even under high-Pi condition to activate or repress transcription, which challenges our current understanding of Pho4 regulation. Wild type and pho4 deletion mutant were grown in low or high phosphate medium and distribution of Rpo21 was analyzed.
2008-12-23 | E-GEOD-13350 | biostudies-arrayexpress