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Multiplexed proteome dynamics profiling of JQ1-PROTAC

ABSTRACT: Goal of this experiment was the differentiation of direct targets of induced degradation of the JQ1-PROTAC from downstream regulatory effects.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD008637 | Pride | 2018-05-02

REPOSITORIES: Pride

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			Action	DRS
	01405_F1_R1_P0135877B02_TMT10.raw.gz	Raw
	01405_F1_R1_P0135877B03_TMT10.raw.gz	Raw
	01405_F1_R1_P0135877B04_TMT10.raw.gz	Raw
	01405_F1_R1_P0135877B05_TMT10.raw.gz	Raw
	01405_F1_R1_P0135877B06_TMT10.raw.gz	Raw

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Publications

Multiplexed Proteome Dynamics Profiling Reveals Mechanisms Controlling Protein Homeostasis.

Savitski Mikhail M MM Zinn Nico N Faelth-Savitski Maria M Poeckel Daniel D Gade Stephan S Becher Isabelle I Muelbaier Marcel M Wagner Anne J AJ Strohmer Katrin K Werner Thilo T Melchert Stephanie S Petretich Massimo M Rutkowska Anna A Vappiani Johanna J Franken Holger H Steidel Michael M Sweetman Gavain M GM Gilan Omer O Lam Enid Y N EYN Dawson Mark A MA Prinjha Rab K RK Grandi Paola P Bergamini Giovanna G Bantscheff Marcus M

Cell 20180315 1

Protein degradation plays important roles in biological processes and is tightly regulated. Further, targeted proteolysis is an emerging research tool and therapeutic strategy. However, proteome-wide technologies to investigate the causes and consequences of protein degradation in biological systems are lacking. We developed "multiplexed proteome dynamics profiling" (mPDP), a mass-spectrometry-based approach combining dynamic-SILAC labeling with isobaric mass tagging for multiplexed analysis of ...[more]

PMID: 29551266

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The effect of an MLK3-targeting PROTAC on protein levels in model breast cancer cell lines.

Project description:The objective of the study was to explore how a new compound (CEP1347-VHL-02 PROTAC) which facilitates the breakdown of mitogen-activated protein kinase kinase kinase 11 (MLK3), affects the protein quantities in the total cell extracts from specific breast cancer cell models. The cell lines used in the study (MCF-7, MDA-MB-468, and HCC1806, the last featuring inducible MLK3 expression) underwent treatment with the PROTAC or matched controls. The data is divided into three subsets, each representing results from a distinct cell line.

2024-10-02 | PXD050260 | Pride

Analysis of HeLa cells after transfection with miR-1, miR-124 and miR-181.

Project description:Analysis of HeLa cells at 24 hours after transfection with wild type miR-1, miR-124, miR-181 versus control transfected HeLa cells. Results were compared to protein down-regulation at 48 hours measured by SILAC-MS. Analysis of HeLa cells at 24 hours after transfection with wild type miR-1, miR-124, miR-181 versus control transfected HeLa cells. Results were compared to protein down-regulation at 48 hours measured by SILAC-MS.

2010-05-25 | E-GEOD-11968 | biostudies-arrayexpress

DT2216 is a specific BCL-XL PROTAC

Project description:To validate the specificity of DT2216, we used the stable isotope labeling with amino acids in cell culture (SILAC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics to analyze the changes in proteins in WI-38 normal human diploid fibroblasts after DT2216 and DT2216NC treatment. The results show that DT2216, but not DT2216NC, reduced the levels of BCL-XL, but none of other proteins were significantly affected by either agent, demonstrating that DT2216 is a specific BCL-XL PROTAC.

2019-10-08 | PXD010878 | Pride

Proteomics analysis with the Aurora-A PROTAC, JB170

Project description:To determine specificity of Aurora-A PROTAC (JB170), MV4-11 cells were labeled with medium containing different stable isotopes (SILAC), treated them with JB170 or Alisertib and subsequently compared their protein content to untreated cells by quantitative mass spectrometry.

2020-09-28 | PXD017342 | Pride

AP-PROTAC-2: a Photoswitchable multi-kinase PROTAC

Project description:Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

2022-09-14 | PXD036224 | Pride

2 Dimensional Thermal proteome profiling of JQ1

Project description:Goal of this experiment was the identification of proteins affected dose dependently in their thermal stability by JQ1.

2018-05-02 | PXD008626 | Pride

Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane treated human breast epithelial cells

Project description:Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study transcriptomic and proteomic changes in the estrogen receptor negative, non tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively. Changes in selected transcripts and proteins were confirmed by PCR and Western blot in MCF10A and MCF12A cells. There was strong correlation between the transcriptomic and proteomic responses in both the SFN treatment (R=0.679, P<0.05) and KEAP1 knockdown (R=0.853, P<0.05) experiments. Common pathways for SFN treatment and KEAP1 knockdown were xenobiotic metabolism and antioxidants, glutathione metabolism, carbohydrate metabolism and NADH/NADPH regeneration. Moreover, these pathways were most prominent in both the transcriptomic and proteomic analyses. The aldo-keto reductase family members, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, as well as NQO1 and ALDH3A1, were highly upregulated at both the transcriptomic and proteomic level. Collectively, these studies served to identify potential biomarkers that can be used in clinical trials to investigate the initial pharmacodynamic action of SFN in the breast. MCF10A cells were treated with SFN or had KEAP1 knocked down by siRNA.

2011-04-22 | E-GEOD-28813 | biostudies-arrayexpress

Development of MDM2-targeting PROTAC technology for advancing bone regeneration

Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.

2024-06-11 | GSE255297 | GEO

Functional characterization of a PROTAC directed against BRAFV600E

Project description:The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation, and survival enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAFV600E have shown great efficacy in the clinic but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC termed P4B displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAFV600E cell lines. In addition, P4B displayed utility in two cell lines harboring alternate BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a rationale for optimizing the drug-like properties of P4B to enable proof of concept studies in vivo.

2020-05-25 | GSE148500 | GEO

Proteomics analysis of a new Cas9-targeting PROTAC molecule

Project description:Scientists have developed several methods to control the activity of Cas protein in a timely way and hence reduce off-target effects, including anti-CRISPR proteins and small molecule inhibitors. The PROTAC is a new conception of using the natural ubiquitin-proteasome system to degrade the protein of interest in drug design and development. Here, we engineered Cas proteins (Cas9, Cas12, and Cas13) by inserting a Phe-Cys-Pro-Phe (FCPF) amino acid sequence (also known as the π-clamp system) and demonstrate that the modified CasFCPF proteins could be labeled in live cells by perfluoroaromatics carrying FITC fluorophore or were degraded by perfluoroaromatics-functionalized PROTAC (PROTAC-FCPF). Proteome-wide analysis of PROTAC-FCPF-mediated Cas9FCPF protein degradation revealed high target specificity, suggesting a wide application of chemically induced proximity in combination with site-specific protein modification in the regulation of protein stability, activity and functionality.

2022-10-18 | PXD022199 | Pride

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