RNA helicase A is necessary for KIF1Bβ tumor suppression in neuroblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE44585 | GEO | 2014/02/05
SECONDARY ACCESSION(S): PRJNA190911
REPOSITORIES: GEO
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Project description:During development neuronal progenitors compete for growth factors such as nerve growth factor NGF and require the prolyl hydroxylase EglN3 and the kinesin KIF1Bβ for developmental apoptosis. Inherited KIF1Bβ loss-of-function mutations in neuroblastomas and pheochromocytomas implicate KIF1Bβ as a 1p36.2 tumor suppressor, however the mechanism of tumor suppression is unknown. We found that KIF1Bβ interacts with the RNA helicase A (DHX9) resulting in DHX9 nuclear accumulation to regulate apoptosis. KIF1Bβ-dependent DHX9 nuclear localization leads to transcription of the apoptotic target XIAP-associated factor 1. DHX9 is induced when NGF is limiting and required for apoptosis in cells deprived of NGF. NB1 cells were transduced to incorporate shRNA against DHX9 or a scrambled control, and transfected with a KIF1Bβ expression vector or control, then transfected cells were isolated and lysed after 48h.
2014-02-05 | E-GEOD-44585 | biostudies-arrayexpress
Project description:While immune responses during nervous system injury and disease are well studied, exactly how primary neurons respond to immune signals is still largely unknown. We find that primary sympathetic neurons respond unexpectedly to interferon-gamma (IFN-γ), a cytokine released by immune cells in response to infection. While IFN-γ induces apoptosis in many cell types, it has the opposite effect on sympathetic neurons by protecting them from apoptotic stimuli. We found that IFN-γ addition enabled sympathetic neurons to become resistant to nerve growth factor (NGF) deprivation- or pan-kinase inhibition-induced apoptosis. In investigating how interferon modulates the apoptotic pathway, we discovered that c-jun phosphorylation and Bim induction in response to NGF deprivation were unchanged with IFN-γ. Downstream of the mitochondria, however, IFN-γ blocked cytochrome c release and caspase-3 activation in NGF-deprived neurons. Microinjection of cytochrome c into XIAP-/- neurons revealed no difference in cell death with IFN-γ addition, demonstrating a role for IFN-γ at the point of mitochondria permeabilization. Levels of Bax and Bcl-XL, molecules that help regulate mitochondrial permeabilization, were unchanged. These results identify Bax activation as the likely point at which IFN-γ acts to inhibit neuronal apoptosis.
2018-12-16 | GSE48683 | GEO
Project description:Nuclear sensor molecules of innate cells recognize pathogenic DNA or RNA to activate innate immunity and defense against bacteria and virus infection. Although some sensors exhibit their preliminary functions in T cells, it is still unclear about the underlying mechanism. Here we found a nuclear sensor-Dhx9, was enhanced its expression in effector CD8 T cells. T cell specific deletion of Dhx9 caused an impaired CD8 T cell expansion, memory formation and virus clearance. Mechanically, Dhx9 could directly regulate id2 transcription and in turn control effector CD8 T cell differentiation. Importantly, Dhx9 could bind to Lck protein, mediate Zap70 phosphorylation, and promoting TCR downstream signaling - ERK pathway to protect effector CD8 T cells from apoptosis. The DSRM and DEXDc-Helicase domain is required for Lck binding and Id2 transcription, respectively. Therefore, we revealed a novel regulatory mechanism that innate nuclear sensor regulates T cell fate and function through modulating adaptive pathways.
2020-11-19 | GSE161697 | GEO
Project description:Collateral lethality occurs when loss of one paralog renders cancer cells dependent on the remaining paralog. Combining genome scale CRISPR/Cas9 screens coupled with RNA-sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase Vaccinia-Related Kinase 1 (VRK1) for their survival. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout in VRK2-expressing cell lines sensitized cells to VRK1 knockout, and conversely, VRK2 overexpression increased cell fitness in VRK1-dependent cell lines upon suppression of VRK1. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas, and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced Barrier-to-Autointegration Factor (BAF) phosphorylation, induced abnormal chromosome segregation. and dysregulated nuclear membrane re-formation following mitosis, resulting in increased DNA damage and apoptosis. Together, these observations identify VRK1 as a synthetic lethal target in VRK2-methylated adult and pediatric gliomas and neuroblastomas.
2022-09-06 | PXD030599 | Pride
Project description:X-linked inhibitor of apoptosis (XIAP) is the most potent endogenous caspase inhibitor preventing cell death via caspase-9, -7 and -3 (initiator and executioner caspase pathways). Using short hairpin RNA (shRNA) against XIAP, stably expressed in a parent HCT116 human colon cancer cell line, a series of clones have been developed. XIAP mRNA levels were established by RT-PCR, the four X (XIAP knockdown) clonal cell lines show 82-93% reduction in XIAP mRNA when compared to the four L (luciferase control) cell lines. Immunoblot analysis showed a 67-89% reduction in XIAP protein in X cell lines compared to L. RNA was analysed by microarray and XIAP knockdown was confirmed in 7 probe sets, there was no significant compensation of other IAP family members. XIAP knockdown induced a 2-fold increase in the basal level of apoptosis without modification of caspase 3/7 activity. Finally, XIAP knockdown sensitises cells to radiotherapy by 20%, to recombinant TRAIL by a 3-fold factor, and to paclitaxel and docetaxel by >2 fold factor. Future work should focus on targeted agents such as rhTRAIL in combination with strategies to down regulate XIAP. XIAP antisense is now in clinical development in oncology.
2008-12-01 | GSE11618 | GEO
Project description:XIAP (X chromosome-linked inhibitor of apoptosis; ILP, BIRC4) is involved not only in apoptosis, but also in signal tranduction in the NF-kappaB, TGF-beta, bone morphogenic protein, and JNK signalling pathways. We have analyzed whether XIAP deletion leads to changes in gene expression, particularly after inflammatory stimulation. Experiment Overall Design: Fibroblasts from wild-type and XIAP knockout mice were analyzed with and without TNFa stimulation (4 hours) using Affymetrix U74Av2 arrays.
2008-11-15 | E-GEOD-3700 | biostudies-arrayexpress
Project description:XIAP (X chromosome-linked inhibitor of apoptosis; ILP, BIRC4) is involved not only in apoptosis, but also in signal tranduction in the NF-kappaB, TGF-beta, bone morphogenic protein, and JNK signalling pathways. We have analyzed whether XIAP deletion leads to changes in gene expression, particularly after inflammatory stimulation. Keywords: genetic modification, inflammatory response
2008-11-12 | GSE3700 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that control protein expression through translational inhibition or mRNA degradation. MiRNAs have been implicated in diverse biological processes such as development, proliferation, apoptosis and differentiation. Upon treatment with nerve growth factor (NGF), rat pheochromocytoma PC12 cells elicit neurite outgrowth and differentiae into neuron-like cells. NGF plays a critical role not only in neuronal differentiation but also in protection against apoptosis. In an attempt to identify NGF-regulated miRNAs in PC12 cells, we performed miRNAM-cM-^@M-^@microarray analysis using total RNAs harvested from cells treated with NGF. In response to NGF treatment, expression of 8 and 12 miRNAs were up- and down-regulated, respectively. Quantitative RT-PCR analysis confirmed increased expression of miR-221, miR-181a* and miR-326, and decreased expression of miR-143, miR-210 and miR-532-3p after NGF treatment, among which miR-221 was drastically up-regulated. Overexpression of miR-221 induced neurite outgrowth of PC12 cells in the absence of NGF treatment, and also enhanced neurite outgrowth caused by low-dose NGF. More importantly, knockdown of miR-221 by antagomir attenuated NGF-mediated neurite outgrowth. Finally, miR-221 decreased expression of Foxo3a and Apaf-1, both of which are involved in apoptosis in PC12 cells. Our results indicate that miR-221 plays a critical role for neuronal differentiation as well as protection against apoptosis in PC12 cells. NGF induced miRNAs expression in rat pheochromocytoma PC12 cells was measured in cells treated with 100 ng/ml NGF for 0, 12, 24 and 48 hr.
2012-05-15 | E-GEOD-32122 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that control protein expression through translational inhibition or mRNA degradation. MiRNAs have been implicated in diverse biological processes such as development, proliferation, apoptosis and differentiation. Upon treatment with nerve growth factor (NGF), rat pheochromocytoma PC12 cells elicit neurite outgrowth and differentiae into neuron-like cells. NGF plays a critical role not only in neuronal differentiation but also in protection against apoptosis. In an attempt to identify NGF-regulated miRNAs in PC12 cells, we performed miRNA microarray analysis using total RNAs harvested from cells treated with NGF. In response to NGF treatment, expression of 8 and 12 miRNAs were up- and down-regulated, respectively. Quantitative RT-PCR analysis confirmed increased expression of miR-221, miR-181a* and miR-326, and decreased expression of miR-143, miR-210 and miR-532-3p after NGF treatment, among which miR-221 was drastically up-regulated. Overexpression of miR-221 induced neurite outgrowth of PC12 cells in the absence of NGF treatment, and also enhanced neurite outgrowth caused by low-dose NGF. More importantly, knockdown of miR-221 by antagomir attenuated NGF-mediated neurite outgrowth. Finally, miR-221 decreased expression of Foxo3a and Apaf-1, both of which are involved in apoptosis in PC12 cells. Our results indicate that miR-221 plays a critical role for neuronal differentiation as well as protection against apoptosis in PC12 cells.
2012-05-16 | GSE32122 | GEO
Project description:miRNA profiling of PC12 rat pheochromocytoma cells during NGF-induced differentiation and apoptosis of differentiated cells after 24h of NGF deprivation. miRNA expression in differentiating and deprivated cells was compared to untreated and terminally differentiated PC12 cells respectivelly. Five-condition experiment, NGF-treated cells (1h, 3h, 6h, 24h, 240h) vs. untreated. One-condition experiment, NGF-deprivated vs. differentiated cells.
2013-05-11 | E-GEOD-46827 | biostudies-arrayexpress