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Changes in proteome upon mTOR activation

ABSTRACT: mTOR activation has been known to affect protein synthesis. To identify molecular signatures in transcriptome that could enhance protein synthesis, RNA-seq and quantitative proteomics studies were conducted using WT and TSC1 null MEFs. In this study, we found that the activation of mTOR leads to genome-wide 3'UTR shortening in mRNAs by alternative polyadenylation and activates ubiquitin-mediated proteolysis. The accession number for the RNA-seq data in this study is SRP056624.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

SUBMITTER: Ebbing de Jong

LAB HEAD: Jeongsik Yong

PROVIDER: PXD002006 | Pride | 2015-06-16

REPOSITORIES: Pride

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			Action	DRS
	Mudpit_jyong_jwchan.mgf	Mgf
	Mudpit_jyong_jwchan.mzid.gz	Mzid
	Mudpit_jyong_jwchan.pride.mgf.gz	Mgf
	Mudpit_jyong_jwchan.pride.mztab.gz	Mztab
	jyong_jwchan_070413_13116_TscTMT_15_27.raw	Raw

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Publications

mRNA 3'-UTR shortening is a molecular signature of mTORC1 activation.

Chang Jae-Woong JW Zhang Wei W Yeh Hsin-Sung HS de Jong Ebbing P EP Jun Semo S Kim Kwan-Hyun KH Bae Sun S SS Beckman Kenneth K Hwang Tae Hyun TH Kim Kye-Seong KS Kim Do-Hyung DH Griffin Timothy J TJ Kuang Rui R Yong Jeongsik J

Nature communications 20150615

Mammalian target of rapamycin (mTOR) enhances translation from a subset of messenger RNAs containing distinct 5'-untranslated region (UTR) sequence features. Here we identify 3'-UTR shortening of mRNAs as an additional molecular signature of mTOR activation and show that 3'-UTR shortening enhances the translation of specific mRNAs. Using genetic or chemical modulations of mTOR activity in cells or mouse tissues, we show that cellular mTOR activity is crucial for 3'-UTR shortening. Although long ...[more]

PMID: 26074333

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Rapamycin effect on Wild Type and TSC deficient Mouse Embryonic Fibroblasts : Time Course

Project description:Aberrant activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a common molecular event in a large variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell intrinsic consequences of mTORC1 activation remain poorly defined. Here, we identify global trancriptional changes in TSC1 and TSC2 null MEFs, which exhibit constitutive activation of mTORC1, compared to wild-type littermate control lines. A rapamycin time course is included to determine those changes that are dependent on mTORC1 signaling, revealing mTORC1 induced and repressed transcripts. In order to identify mTORC1-dependent transcriptional changes, we compared wild-type MEFs to both Tsc1-/- and Tsc2-/- MEFs following serum starvation, where mTORC1 signaling is off in wild-type cells and fully active in TSC-deficient cells. All cell lines were serum-starved for 24 h, and the Tsc1-/- and Tsc2-/- cells were treated with a time course of rapamycin prior to the isolation of mRNA for microarray analysis. Immortalized wild-type (Tsc2+/+ p53-/-), Tsc1-/- (p53+/+, 3T3-immortalized), and Tsc2-/- (p53-/-, derived from a littermate of the wild-type cell line) MEFs are the three cell lines used in this study and were derived in the laboratory of David J. Kwiatkowski (Brigham and Women's Hospital, Harvard Medical School, Boston, MA). Wild-type and null MEFs were grown to 70% confluence in 10 cm plates and were serum starved for 24 h in the presence of vehicle (DMSO) for 24 h or rapamycin (20 nM) for 2, 6, 12, or 24 h. All vehicle-treated samples (0 h time points) were plated in triplicate and all rapamycin time course samples were plated in duplicate. For each replicate, expression analysis was performed by hybridization to an Affymetrix Mouse 430_2 oligonucleotide microarray chip.

2010-07-30 | E-GEOD-21755 | biostudies-arrayexpress

Rapamycin effect on Wild Type and TSC deficient Mouse Embryonic Fibroblasts : Time Course

2010-07-30 | GSE21755 | GEO

Tumor Suppressor TSC1 Negatively Regulates Polo-like Kinase Expression and Controls the Balance of Schwann Cell Proliferation and Differentiation

Project description:Activation of mTOR signaling by Tsc1 ablation during early developmental stages increases SC proliferation and delays radial sorting, while causing hypomyelination in the PNS. However, knockout Tsc1 in myelinating SCs at postnatal stages promotes myelin overgrowth and outfoldings. Sustained mTOR pathway leads to activation of the PLK signaling pathway. mTOR attenuation or pharmacological inhibition of PLK1 could partially rescue myelination defects in Tsc1 mutant sciatic nerves. Our data suggest that TSC1-mTOR maintains the homeostasis of SC proliferation and differentiation in a stage-specific manner.

2018-09-05 | GSE103957 | GEO

Regulation of PERK-eIF2Î± Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

Project description:Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERKâeIF2Î± dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis. Gene expression profiling of optic nerve from P12 control and Tsc1cKO mice

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mTORC1 regulates microRNA biogenesis in mouse embryonic fibroblast cells

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Genome and Targeted Sequencing of Bladder Cancer

Project description:<p>One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.</p>

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Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice

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Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).

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