Discovery of inhibitors of the HSP90-Calcineurin-NFAT pathway against glioblastoma
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ABSTRACT:
PROVIDER: PRJNA428485 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6440540_1.fastq.gz | Fastqsanger.gz | |||
| SRR6440540_2.fastq.gz | Fastqsanger.gz | |||
| SRR6440531_1.fastq.gz | Fastqsanger.gz | |||
| SRR6440531_2.fastq.gz | Fastqsanger.gz | |||
| SRR6440541_1.fastq.gz | Fastqsanger.gz |
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Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common form of lymphoma. We could show that in DLBCL cell lines the transcription factor NFAT is constitutively activated and drives the survival of a DLBCL subset. Aim of the analysis was to identify NFAT target genes in a NFAT-dependent (HBL-1) or -independent (HT) DLBCL cell line. To block NFAT activity, the DLBCL cells were treated with the calcineurin inhibitor cyclosporin A (CsA) up to 48 h. With this approach, we identified several survival-related NFAT target genes in HBL-1 cells that might explain the toxic effects of calcineurin inhibitors.
2019-11-23 | GSE140882 | GEO
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates
2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress
Project description:We report the application of mRNA sequencing technology for high-throughput profiling of genes expression changes in U87 glioblastoma cells after treatment with compound YZ129 that we identified in our screen. By analyzing the total mRNA sequencing between YZ129 treatment group and the DMSO control group, we identified that 181 genes were significantly downregulated (changed >2 folds), while 226 genes were significantly upregulated (changed >2 folds). The downregulated genes were mainly associated with hypoxia (ALDOC, TMEM45A, F3, FOS, GFBP1, etc), glycolysis (SLC2A1, ANGPTL4, ENO2, LDHA, PGM, PFKFB3, etc.), PI3K/AKT/mTOR pathway (AK4, SLC2A1, PDK1, PGM1, PLOD2, TUBA4A, etc.), EMT (epithelial-mesenchymal transition) (VEGFA, ID2, COL1A1, FOXC2, LOXL2, etc.), G2/M checkpoint (UBE2C, FBXO5 (Emi1), TOP2A, MCM5/6), etc. some of the upregualted genes may contribute to the possible chemoresistance, such as FOSB, INHBA, EDN1, IRS2, KDM6B. This study yields a global view on molecular response to YZ29 treatment in GBM cells at mRNA level.
2018-10-01 | GSE108749 | GEO
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A.
2011-10-01 | GSE29094 | GEO
Project description:Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM. YZ129-induced GBM cell-cycle arrest at the G2/M phase promoted apoptosis and inhibited tumor cell proliferation and migration. At the molecular level, YZ129 directly engaged HSP90 to antagonize its chaperoning effect on calcineurin to abrogate NFAT nuclear translocation, and also suppressed other proto-oncogenic pathways including hypoxia, glycolysis, and the PI3K/AKT/mTOR signaling axis. Our data highlight the potential for targeting the cancer-promoting HSP90 chaperone network to treat GBM.
| S-EPMC6430684 | biostudies-literature
Project description:Complex regulatory mechanisms control continuous maintenance of myeloid progenitors and renewal of differentiated cells. Transcription factors play a important role in these processes. Here we report that the activation the calcineurin-NFAT signaling pathway inhibit the proliferation of myeloid granulocyte-monocyte progenitor (GMP). Myeloid progenitor subtypes possessed different susceptibilities to Ca2+ flux induction and consequently differential engagement of the calcineurin-NFAT pathway. This study show that inhibition of the calcineurin-NFAT pathway enhanced proliferation of GMPs both in vivo and in vitro. The calcineurin-NFAT signaling in GMPs is initiated through Flt3-L. The inhibition of the calcineurin-NFAT pathway altered the expression of the cell cycle regulation genes CDK4, CDK6, and CDKN1A, thus enabling faster cell cycle progression. The extensive use of NFAT inhibitors in the clinic should take into account that, in addition to the immunosuppression role in lymphoid cells, these NFAT inhibitors also affect the maintenance of the myeloid compartment. Microarray technology was used to understand the effects of NFAT inhibitors on C-kit enriched lineage negative cells.
2014-12-31 | GSE47208 | GEO
Project description:Self-renewal and pluripotency are hallmarks of embryonic stem cells (ESCs). However, signaling pathways triggering their transition from self-renewal to differentiation are not well defined. Here, we report that the calcineurin-NFAT signaling pathway is both necessary and sufficient to switch ESCs from an undifferentiated state to early differentiation.To gain an insight into the function of calcinerin-NFAT signaling in ESC lineage commitment, we examined the repertoire of genes changed after LIF withdrawal alone, LIF withdrawal in the presence of cyclosporine A (CsA), a specific inhibitor of calcinerin and forced expression of active forms of calcineurin (deltaCnA) in the presence of LIF,and identified distinct classes of up and down regulated genes by calcineurin-NFAT signaling in mouse embryonic stem cells.
2011-01-01 | GSE21378 | GEO
Project description:Inhibition of calcineurin-NFAT pathway at the early stage can block somatic cell reprogramming. In order to study how the calcineurin-NFAT pathway contributes to the early stage of reprogramming, we designed this microarray experiment and tried to find out which genes or signalings were changed after inhibition of calcineurin-NFAT signaling by CSA (a specific inhibitor of calcineurin-NFAT pathway).
2015-12-01 | GSE67739 | GEO
Project description:Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. Our previous study showed that this pathway plays a critical role in mouse embryonic stem cell (mESC) differentiation. However, its function in human ESCs (hESCs) remains unclear. Here, we report that expression of PPP3CC, the gene encoding the catalytic subunit of calcineurin, increases along with the process of hESC differentiation, and its knockdown (KD) enhances the self-renewal ability of hESCs with a simultaneous reduction in the expression of differentiation-associated markers regardless of culture conditions. Moreover, we observed that NFATC3 translocates from the cytoplasm to the nucleus when hESCs exit from a self-renewal state. These results indicate that calcineurin-NFAT signaling is activated and required during hESC differentiation. Mechanistically, we also found that in hESCs NFATC3 interacts with JUN， one of AP-1 complex subunit, and co-expression of exogenous NFATC3 and JUN upregulates lineage markers remarkably even under a self-renewal culture condition. Additionally, inhibition of this cascade represses MAPK signaling rapidly, including ERK1/2, JNK and P38. Taken together, this study delineates the importance of the calcineurin-NFATC3/JUN signaling cascade for the pluripotency maintenance of hESCs.
2020-08-04 | GSE155563 | GEO
Project description:Self-renewal and pluripotency are hallmarks of embryonic stem cells (ESCs). However, signaling pathways triggering their transition from self-renewal to differentiation are not well defined. Here, we report that the calcineurin-NFAT signaling pathway is both necessary and sufficient to switch ESCs from an undifferentiated state to early differentiation.To gain an insight into the function of calcinerin-NFAT signaling in ESC lineage commitment, we examined the repertoire of genes changed after LIF withdrawal alone, LIF withdrawal in the presence of cyclosporine A (CsA), a specific inhibitor of calcinerin and forced expression of active forms of calcineurin (deltaCnA) in the presence of LIF,and identified distinct classes of up and down regulated genes by calcineurin-NFAT signaling in mouse embryonic stem cells. Total RNA obtained from CGR8 ES cells under the following conditions: withdrawal of LIF for 0, 1 and 3 days; withdrawal of LIF for 0, 1 and 3 days in the presence of CsA, and induced expression of deltaCnA by withdrawal of Tc for 0, 1 and 4 days in ideltaCnAES cells.Hybridized to Illumina Sentrix Mouse-6 v1.1 Beadhips
2011-01-01 | E-GEOD-21378 | biostudies-arrayexpress