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Chemical Genetics of TOR Identifies an SCF Family E3 Ubiquitin Ligase Inhibitor

ABSTRACT: The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyper-activation of the mTOR pathway in human cancers, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based high-throughput chemical genetic screen to identify small-molecule enhancers of rapamycin (SMERs) and used whole genome expression analysis to identify their mechanisms of action. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Saccharomyces cerevisiae Schizosaccharomyces pombe

PROVIDER: GSE22272 | GEO | 2011/06/30

SECONDARY ACCESSION(S): PRJNA128719

REPOSITORIES: GEO

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Chemical Genetics of TOR Identifies an SCF Family E3 Ubiquitin Ligase Inhibitor

Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyper-activation of the mTOR pathway in human cancers, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based high-throughput chemical genetic screen to identify small-molecule enhancers of rapamycin (SMERs) and used whole genome expression analysis to identify their mechanisms of action. This SuperSeries is composed of the following subset Series: GSE22270: Expression data from Saccharomyces cerevisiae Met30 temperature-sensitive strain GSE22271: Expression data from Saccharomyces cerevisiae temperature-sensitive strains specific for SCF core components (Skp1, Cullin (Cdc53), E2 enzyme (Cdc34)) and the F-box protein Cdc4. Refer to individual Series

2011-06-30 | E-GEOD-22272 | biostudies-arrayexpress

Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase.

Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyperactivation of the mammalian TOR (mTOR) pathway in human cancers, strategies to enhance TOR pathway inhibition are needed. We used a yeast-based screen to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor (SMER3) of the Skp1-Cullin-F-box (SCF)(Met30) ubiquitin ligase, a member of the SCF E3-ligase family, which regulates diverse cellular processes including transcription, cell-cycle control and immune response. We show here that SMER3 inhibits SCF(Met30) in vivo and in vitro, but not the closely related SCF(Cdc4). Furthermore, we demonstrate that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and show evidence for SMER3 directly binding to Met30. Our results show that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes.

| S-EPMC2902569 | biostudies-literature

A Cullin1-based SCF E3 ubiquitin ligase targets the InR/PI3K/TOR pathway to regulate neuronal pruning.

Project description:Pruning that selectively eliminates unnecessary axons/dendrites is crucial for sculpting the nervous system during development. During Drosophila metamorphosis, dendrite arborization neurons, ddaCs, selectively prune their larval dendrites in response to the steroid hormone ecdysone, whereas mushroom body ? neurons specifically eliminate their axon branches within dorsal and medial lobes. However, it is unknown which E3 ligase directs these two modes of pruning. Here, we identified a conserved SCF E3 ubiquitin ligase that plays a critical role in pruning of both ddaC dendrites and mushroom body ? axons. The SCF E3 ligase consists of four core components Cullin1/Roc1a/SkpA/Slimb and promotes ddaC dendrite pruning downstream of EcR-B1 and Sox14, but independently of Mical. Moreover, we demonstrate that the Cullin1-based E3 ligase facilitates ddaC dendrite pruning primarily through inactivation of the InR/PI3K/TOR pathway. We show that the F-box protein Slimb forms a complex with Akt, an activator of the InR/PI3K/TOR pathway, and promotes Akt ubiquitination. Activation of the InR/PI3K/TOR pathway is sufficient to inhibit ddaC dendrite pruning. Thus, our findings provide a novel link between the E3 ligase and the InR/PI3K/TOR pathway during dendrite pruning.

| S-EPMC3775723 | biostudies-literature

Expression data from Saccharomyces cerevisiae temperature-sensitive strains specific for SCF core components (Skp1, Cullin (Cdc53), E2 enzyme (Cdc34)) and the F-box protein Cdc4.

2011-06-30 | GSE22271 | GEO

Expression data from Saccharomyces cerevisiae temperature-sensitive strains specific for SCF core components (Skp1, Cullin (Cdc53), E2 enzyme (Cdc34)) and the F-box protein Cdc4.

Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyper-activation of the mTOR pathway in human cancers, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based high-throughput chemical genetic screen to identify small-molecule enhancers of rapamycin (SMERs) and used whole genome expression analysis to identify their mechanisms of action. We incubated various temperature-sensitive yeast strains at either the permissive (room temperature) or non-permissive (35°C) temperature for 1 hour prior to RNA extraction and hybridization on Affymetrix microarrays. Comparison of expression profiles enabled identification of gene-signatures specific to inhibition of each gene product.

2011-06-30 | E-GEOD-22271 | biostudies-arrayexpress

Computationally designed peptide inhibitors of the ubiquitin E3 ligase SCF(Fbx4).

Project description:A structure-based computational approach was used to rationally design peptide inhibitors that can target an E3 ligase (SCF(Fbx4) )-substrate (TRF1) interface and subsequent ubiquitylation. Characterization of the inhibitors demonstrates that our sequence-optimization protocol results in an increase in peptide-TRF1 affinity without compromising peptide-protein specificity.

| S-EPMC4028150 | biostudies-literature

The centrosomal E3 ubiquitin ligase FBXO31-SCF regulates neuronal morphogenesis and migration.

Project description:Neuronal development requires proper migration, polarization and establishment of axons and dendrites. Growing evidence identifies the ubiquitin proteasome system (UPS) with its numerous components as an important regulator of various aspects of neuronal development. F-box proteins are interchangeable subunits of the Cullin-1 based E3 ubiquitin ligase, but only a few family members have been studied. Here, we report that the centrosomal E3 ligase FBXO31-SCF (Skp1/Cullin-1/F-box protein) regulates neuronal morphogenesis and axonal identity. In addition, we identified the polarity protein Par6c as a novel interaction partner and substrate targeted for proteasomal degradation in the control of axon but not dendrite growth. Finally, we ascribe a role for FBXO31 in dendrite growth and neuronal migration in the developing cerebellar cortex. Taken together, we uncovered the centrosomal E3 ligase FBXO31-SCF as a novel regulator of neuronal development.

| S-EPMC3585373 | biostudies-literature

Differentially regulated genes in TOR knockdown Arabidopsis lines

2012-12-18 | GSE42968 | GEO

SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination.

Project description:Homeostasis of meiotic DNA double strand breaks (DSB) is critical for germline genome integrity and homologous recombination. Here we demonstrate an essential role for SKP1, a constitutive subunit of the SCF (SKP1-Cullin-F-box) ubiquitin E3 ligase, in early meiotic processes. SKP1 restrains accumulation of HORMAD1 and the pre-DSB complex (IHO1-REC114-MEI4) on the chromosome axis in meiotic germ cells. Loss of SKP1 prior to meiosis leads to aberrant localization of DSB repair proteins and a failure in synapsis initiation in meiosis of both males and females. Furthermore, SKP1 is crucial for sister chromatid cohesion during the pre-meiotic S-phase. Mechanistically, FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells. Our results support a model wherein the SCF ubiquitin E3 ligase prevents hyperactive DSB formation through proteasome-mediated degradation of HORMAD1 and subsequent modulation of the pre-DSB complex during meiosis.

| S-EPMC9122608 | biostudies-literature

Differentially regulated genes in TOR knockdown Arabidopsis lines

Project description:Rapamycin-sensitive transgenic Arabidopsis lines (BP12) expressing yeast FK506 Binding Protein12 (FKBP12) were developed. Inhibition of TOR in BP12 plants by rapamycin resulted in slower overall root, leaf and shoot growth and development leading to poor nutrient uptake and light energy utilization. Genetic and physiological studies together with RNA-Seq and metabolite analysis of TOR-suppressed lines revealed that TOR regulates development and lifespan in Arabidopsis by restructuring cell growth, carbon and nitrogen metabolism, gene expression, ribosomal RNA and protein synthesis. Arabidopsis WT (Col)and BP12-2 (TOR knockdown line) seedlings at 15 DAG were treated with rapamycin for 3 days by transferring from 0.5 MS medium to 0.5 MS+10 ug/ml rapamycin. Triplicate samples of rapamycin treated WT and BP12-2 seedlings were used for RNA-Seq analysis (Illumina Hiseq 2000). Paired-end alignments were obtained through aligning short reads onto the reference Arabidopsis Genome (TAIR9) using Bowtie. More than 80% of the reads mapped onto the genome. Htseq-count was used to count the reads from the Bowtie derived output files. Differential expressed genes were identified using edgeR. The FDR-corrected P value for differential expression was set to be <=0.05.

2012-12-18 | E-GEOD-42968 | biostudies-arrayexpress

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