Messenger (m)RNA export from the nucleus is essential for eukaryotic gene expression. Here, we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases the nuclear export of RAD51 mRNA, and RAD51 protein abundance, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans.
Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity.
Cell line
View SamplesGene expression variation upon folate deficiency and repletion in human foreskin keratinocytes immortalized by HPV16E6E7 Overall design: Effects of folate modulation on several cellular events such as DNA stability
Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes.
Specimen part, Subject
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Skeletal muscle microRNA and messenger RNA profiling in cofilin-2 deficient mice reveals cell cycle dysregulation hindering muscle regeneration.
Specimen part
View SamplesmRNA Expression in Quadriceps Muscle from Cofilin-2 Null Mice Compared to WT Littermates on Day 7
Skeletal muscle microRNA and messenger RNA profiling in cofilin-2 deficient mice reveals cell cycle dysregulation hindering muscle regeneration.
Specimen part
View SamplesExpression of the MT1-MMP gene induces a significant upregulation of of oncogenes and tumorignenic genes in 184B5-MT1 cells.
Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells.
Cell line
View SamplesWe perfomed single-cell RNA-sequnecing of around 10,000 cells from normal human liver tissue to construct a human liver cell atlas. We reveal previously unknown subtypes in different cell type compartments. We also use our normal liver cell atlas to infer perturbed phenoytpes of cells from HCC samples, human cells engrafted into a mouse liver and liver organoids. Overall design: Single cells were isolated from human liver resection specimens and then sorted by FACS into 384 well plates in a unbiased way and on the basis of cell surface markers for distinct cell types. ScRNA-seq was done using the mCelSeq2 protocol cellbarcodes_cellid.csv Supplemetary file contains cellds and one of the 192 unique cellbarcode associated with the cellid.
A human liver cell atlas reveals heterogeneity and epithelial progenitors.
Specimen part, Subject
View SamplesAdvanced ovarian cancers are initially responsive to chemotherapy with platinum drugs but develop drug resistance in most cases. We showed recently that hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and that this effect is mediated by the p38 mitogen-activated protein kinase. In this work, we integrated genome-wide expression profiling, in silico data survey, and functional assays to identify transcripts regulated in SK-OV-3 ovarian cancer cells made more responsive to CDDP by HGF. Using oligonucleotide microarrays, we found that HGF pretreatment changes the transcriptional response to CDDP. Quantitative reverse transcription-PCR not only validated all the 15 most differentially expressed genes but also confirmed that they were primarily modulated by the combined treatment with HGF and CDDP and reversed by suppressing p38 mitogen-activated protein kinase activity. Among the differentially expressed genes, we focused functional analysis on two regulatory subunits of the protein phosphatase 2A, which were down-modulated by HGF plus CDDP. Decrease of each subunit by RNA interference made ovarian cancer cells more responsive to CDDP, mimicking the effect of HGF. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or revert chemotherapy resistance.
Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin.
Cell line
View Samplesp63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC syndrome, ADULT syndrome and AEC syndrome . The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. We report a study on the TAp63a isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63a wt, DeltaNp63 alpha or the TAp63 alpha-Q540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63a and causes misregulation of genes involved in the control of cell growth and epidermal differentiation.
The Hay Wells syndrome-derived TAp63alphaQ540L mutant has impaired transcriptional and cell growth regulatory activity.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma.
No sample metadata fields
View SamplesFollicular Lymphomas are blood tumors growing as spheres in patients. Before this study, there was no experimental model mimicking the 3D organization of these in vivo tumors. We develop such a model, called MALC, and observed a progressive enrichment in quiescent cells in these with time of culture; these cells were sorted, as their cycling counterparts, and their transcriptomes were compared. We used microarrays to detail the differential global gene expression profile between quiescent and cycling cells isolated from MALC.
Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma.
No sample metadata fields
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