Similar Datasets
Project description:Effects of rapamycin, torin1, and rapalink1 on RNA levels
| PRJNA955188 | ENA
Project description:This study aimed to identify changes in protein level after inhibiting the mechanistic target of rapamycin using mass spectrometry analysis
2023-07-27 | PXD041933 | Pride
Project description:Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, which in turn contributes to longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Cells lacking the GATA transcription factor Gaf1 (gaf1Δ) grew normally even in high doses of Torin1. The gaf1Δ mutation shortened the chronological lifespan of non-dividing cells and diminished the longevity triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, upon TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation. Surprisingly, Gaf1 bound to, and down-regulated the tRNA genes, so also functions as a transcription factor for genes transcribed by RNA polymerase III. Thus, Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1.
2020-03-02 | E-MTAB-8569 | biostudies-arrayexpress
Project description:Inhibition of mechanistic target of rapamycin (mTOR) constitutes the standard of care of lymphangioleiomyomatosis (LAM). However, this treatment does not eradicate diseased cells and some patients show progressive decline of lung function. This study provides preclinical evidence for beneficial therapeutic approaches in combination with rapamycin. LAM tumorigenesis is reduced in vivo (ELT3-V3 tumor xenografts) using approved drugs for other human diseases and targeting monoamine oxidase A (MAO-A; clorgyline) or MAO-B (rasagiline).
2019-10-01 | GSE129399 | GEO
Project description:mTOR inhibitor rapamycin is a well-known anticancer and immunosuppressant agent. Effects of rapamycin on zebrafish cells have not been previously studied using transcriptome analyses. Our microarray analysis on ZF4 cells showed that rapamycin treatment modulated a large set of genes with varying functions including protein synthesis, assembly of mitochondrial and proteosomal machinery, cell cycle, metabolism, and oxidative phosphorylation.
2016-12-31 | GSE53086 | GEO
Project description:Rapamycin is a naturally occurring macrolide whose target is at the core of nutrient and stress regulation in a wide range of species. Despite well-established roles as an inhibitor of cap-dependent mRNA translation, relatively little is known about its effects on other modes of RNA processing. Here, we characterize the landscape of rapamycin-induced post-transcriptional gene regulation. Transcriptome analysis of rapamycin-treated cells revealed genome-wide changes in alternative mRNA splicing and pronounced changes in NMD-sensitive isoforms. We demonstrate that despite well-documented attenuation of cap-dependent mRNA translation, rapamycin can augment NMD of certain transcripts. Rapamycin-treatment significantly reduces the levels of both endogenous and exogenous PTC-containing mRNA isoforms and its effects are dose-, UPF1- and 4EBP-dependent manner. The PTC-containing SRSF6 transcript exhibits a shorter half-life upon rapamycin-treatment as compared to the non-PTC isoform. Rapamycin-treatment also caused depletion of PTC-containing mRNA isoforms from polyribosomes, underscoring the functional relationship between translation and NMD. Enhanced NMD activity also correlates with an enrichment of the nuclear Cap Binding Complex (CBC) in rapamycin-treated cells. Our data demonstrate that rapamycin modulates global RNA homeostasis by NMD.
2016-11-11 | GSE89774 | GEO
Project description:Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulation of the primary human trophoblast cell transcriptome
| PRJNA771456 | ENA
Project description:Tuberous sclerosis complex (TSC) is an inherited multi-system disorder caused by mutations in the TSC1 or TSC2 gene. TSC patients are often diagnosed with a range of neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD), intellectual disability (ID), anxiety and mood disorders. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using neural progenitor cells (NPCs) from patient-derived induced pluripotent stem cells (iPSCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in CRISPR-modified TSC1-null NPCs, which were unaffected by mTORC1 inhibition by rapamycin,the only approved therapy for TSC1. Here, to assess TSC1-dependent gene expression programs in NPCs, we used polysome-profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level. In addition to changes in mRNA abundance, this revealed numerous TSC1-dependent alterations in translational efficiencies. To assess the relevance of these gene expression alterations we performed polysome-profiling in post-mortem brains originating from ASD donors and matched controls. Strikingly, TSC1-dependent alterations in mRNA translation observed in NPCs were largely recapitulated in human brains. Furthermore, although polysome-profiling revealed a partial reversal of TSC1-associated gene expression alterations following rapamycin treatment, most genes related to neural activity/synaptic regulation or ASD that showed TSC1-dependent translation were rapamycin-insensitive. Therefore, we also examined whether early ND rapamycin-insensitive phenotypes in TSC1-null NPCs could be rescued by a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272 (Revolution Medicines, Inc.). Unlike rapamycin, RMC-6272 strongly inhibited translation and reversed TSC1-associated proliferation and neurite outgrowth phenotypes. In summary, we reveal ample translational alterations in TSC1 patient-derived NPCs recapitulating human brain expression profiles and potential implications for treatment of TAND.
2023-10-27 | GSE239412 | GEO
Project description:Determination of RNAPII, Rrd1-Myc, RNAPII-Ser2-P, RNAPII-Ser5-P abundance between wildtype and rrd1 deletion strains under rapamycin or control treatments.Rapamycin is an anticancer agent and immunosuppressant that acts by inhibiting the TOR signaling pathway. In yeast, rapamycin mediates a profound transcriptional response for which the RRD1 gene is required. To further investigate this connection, we performed genome-wide association studies of RNA polymerase II (RNAPII) and Rrd1 in response to rapamycin and demonstrate that Rrd1 colocalizes with RNAPII on actively transcribed genes and both are recruited to rapamycin responsive genes. Strikingly, when Rrd1 is lacking, RNAPII remains inappropriately associated to ribosomal genes and fails to be recruited to rapamycin responsive genes. This occurs independently of TATA box binding protein recruitment. Furthermore, Rrd1 modulates the phosphorylation status of RNAPII CTD and additional evidence suggests that Rrd1 is involved in various transcriptional stress responses. We propose that Rrd1 is a novel transcription elongation factor that fine-tunes the transcriptional stress response of RNAPII.
2010-11-30 | E-MEXP-2763 | biostudies-arrayexpress
Project description:Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis. Total RNA obtained from 2-4 male mice of each analysed group (25 weeks old controls, 25 month old controls, 25 month old rapamycin treated)
2013-07-29 | E-GEOD-41018 | biostudies-arrayexpress