The SCP FBXO42 CCDC6 axis regulates cancer cell mitosis via proteasomal degradation of PP2A
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Eclipse
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Christopher Rose
PROVIDER: MSV000094889 | MassIVE | Wed May 29 11:43:00 BST 2024
REPOSITORIES: MassIVE
Similar Datasets
Project description:Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells upregulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdc2. In this study we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A but leads to relief of negative feedback inhibition and activation of Wee1-Cdc2 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effectors, like PP2A and Wee1, may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors Biological triplicate of PC3 treated with siClusterin were compared to biological trplicate of PC3 treated with siScramblein
2016-03-01 | E-GEOD-67256 | biostudies-arrayexpress
Project description:Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells upregulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdc2. In this study we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A but leads to relief of negative feedback inhibition and activation of Wee1-Cdc2 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effectors, like PP2A and Wee1, may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors
2016-03-01 | GSE67256 | GEO
Project description:The incidence for pancreatic ductal adenocarcinoma (PDAC) is rising which has a low survival rate. In cancer, Epithelial-to-Mesenchymal transition (EMT) contribute to an aggressive phenotype. Protein Phosphatase Type 2A (PP2A) are initially regarded as tumor suppressors, the connection with EMT in patients is uncertain. We investigated the relation of a ‘PP2A’ gene signature (en-compassing catalytic, structural and regulatory subunits; and endogenous PP2A inhibitors and activators) with EMT in PDAC patients. We could demonstrate a link between PDAC and EMT in four patient datasets using datamining, correlation study and gene set analysis. Furthermore, we identified a strong association of PP2A with EMT in advanced pancreatic cancer patients and in particular a significant upregulation of PP2A inhibitor genes in aggressive/EMT-high PDAC. In vitro, pharmacological inhibition of PP2A through Okadaic acid induced EMT in human pancreatic cells. Two different cell models were developed and their morphology, gene and protein expression determined. In the more advanced OA-induced EMT model (OA7G), statistical changes in proteins of natural PP2A-inhibitors was observed and this requires further investigations. Translationally, these observations indicate that PP2A could be a central factor in cancer and it is therefore attractive to test compounds that can target PP2A enzyme activity in PDAC.
2023-07-20 | PXD037976 | Pride
Project description:Entry into and exit from mitosis is driven by precisely-timed changes in protein abundance, and involves transcriptional regulation and protein degradation. However, the role of translational regulation in modulating cellular protein content during mitosis remains poorly understood. Here, using ribosome profiling, we show that translational, rather than transcriptional regulation is the dominant mechanism for modulating protein synthesis at mitotic entry. The vast majority of regulated mRNAs are translationally repressed, which contrasts previous findings of selective mRNA translational activation at mitotic entry. One of the most pronounced translationally repressed genes in mitosis is Emi1, an inhibitor of the anaphase promoting complex (APC), which is degraded during mitosis. We show that Emi1 degradation is insufficient for full APC activation and that simultaneous translational repression is required. These results provide a genome-wide view of protein translation during mitosis and suggest that translational repression may be used to ensure complete protein inactivation Ribosome profiling and mRNA-seq from 3 time points in the cell cycle
2015-09-01 | E-GEOD-67902 | biostudies-arrayexpress
Project description:ADP-ribosylation is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteostasis. While the roles of ADPr transferases such as PARP1/2 and TNKS1/2 are well established, the functions and regulatory mechanisms of ADPr hydrolases are still poorly understood. Here, we identify a previously uncharacterized function of the poly(ADP-ribose) glycohydrolase PARG in regulating protein degradation. Using quantitative proteomics, we show that PARG inhibition depletes protein levels of the mono-ADPr hydrolase TARG1. We demonstrate that this TARG1 depletion is both PAR- and proteasome-dependent, and identify the E3 ubiquitin ligases HUWE1 and TRIP12 as mediators of this process. Our findings establish TARG1 as a substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism controlling its stability. This work highlights a new dimension of interplay between the two ADP-ribosyl hydrolases, with implications for the refinement of PARG-targeted therapeutic strategies.
2025-11-25 | GSE310746 | GEO
Project description:Similar to ubiquitin, SUMO forms chains, but the identity of SUMO-chain-modified factors and the purpose of this modification remain largely unknown. Here, we identify budding yeast SUMO protease Ulp2, able to disassemble SUMO chains, as a DDK interactor enriched at replication origins that promotes DNA replication initiation. Replication-engaged DDK is SUMOylated on chromatin, becoming a degradation-prone substrate when Ulp2 no longer protects it against SUMO-chain assembly. Specifically, SUMO chains channel DDK for SUMO-targeted ubiquitin ligase Slx5/Slx8-mediated and Cdc48 segregase-assisted proteasomal degradation. Importantly, the SUMOylation-defective ddk-KR mutant rescues inefficient replication onset and MCM activation in cells lacking Ulp2, suggesting that SUMO chains time DDK degradation. Using two unbiased proteomic approaches, we further identify subunits of the MCM helicase and other factors as SUMO-chain-modified degradation-prone substrates of Ulp2 and Slx5/Slx8. We thus propose SUMO-chain-/Ulp2-protease-regulated proteasomal degradation as a mechanism that times the availability of functionally-engaged SUMO-modified protein pools during replication and beyond.
2019-09-10 | GSE113835 | GEO
Project description:Glioblastoma (GBM) is an incurable cancer despite aggressive treatment paradigms. Current immunotherapies, such as CTLA-4 and/or PD-1 blockade, have yet to demonstrate benefits for GBM. A key barrier is the immunologically “cold” nature of GBM defined by insufficient tumor antigen presentation and lack of T cells infiltration. We previously demonstrated that pharmacologic inhibition of Protein Phosphatase-2A (PP2A), using a small molecule inhibitor, synergized with PD1 blockade in multiple preclinical tumor models including GBM. However, PP2A is ubiquitously expressed in many cell types and regulates many cellular pathways. The cell type or molecular mechanism responsible for PP2A-modulated tumor immunity is poorly understood. Here, we demonstrate that genetic ablation of PP2A in glioma cells sufficiently promotes tumor immunogenicity by enhancing 1) dsDNA production and thereby cGAS-Type I interferon (IFN) signaling, 2) MHC-I expression and 3) tumor mutational burden. PP2A deficient glioma enhances DC activation and cross presentation to promote clonal expansion of tumor antigen specific CD8 cells. PP2A deficiency also markedly sensitize tumors to immune checkpoint blockade and radiotherapy. Single cell analysis of murine glioma demonstrates that PP2A deficient tumors have 1) increased infiltration of CD8+ T cell, NK cell and cDC1 cells, 2) reduced infiltration of immunosuppressive tumor associated macrophages, 3) promotion of IFN signaling in both myeloid and tumor cells, and 4) reduced glioma-associated gene signature that predicts poor prognosis in glioma patients. This is the first study to establish a role for PP2A in regulating dsDNA-cGAS-STING signaling and collectively, our results suggest that PP2A is a promising novel target to enhance anti-tumor immunity for glioma.
2023-05-17 | GSE213308 | GEO
Project description:Glioblastoma (GBM) is an incurable cancer despite aggressive treatment paradigms. Current immunotherapies, such as CTLA-4 and/or PD-1 blockade, have yet to demonstrate benefits for GBM. A key barrier is the immunologically “cold” nature of GBM defined by insufficient tumor antigen presentation and lack of T cells infiltration. We previously demonstrated that pharmacologic inhibition of Protein Phosphatase-2A (PP2A), using a small molecule inhibitor, synergized with PD1 blockade in multiple preclinical tumor models including GBM. However, PP2A is ubiquitously expressed in many cell types and regulates many cellular pathways. The cell type or molecular mechanism responsible for PP2A-modulated tumor immunity is poorly understood. Here, we demonstrate that genetic ablation of PP2A in glioma cells sufficiently promotes tumor immunogenicity by enhancing 1) dsDNA production and thereby cGAS-Type I interferon (IFN) signaling, 2) MHC-I expression and 3) tumor mutational burden. PP2A deficient glioma enhances DC activation and cross presentation to promote clonal expansion of tumor antigen specific CD8 cells. PP2A deficiency also markedly sensitize tumors to immune checkpoint blockade and radiotherapy. Single cell analysis of murine glioma demonstrates that PP2A deficient tumors have 1) increased infiltration of CD8+ T cell, NK cell and cDC1 cells, 2) reduced infiltration of immunosuppressive tumor associated macrophages, 3) promotion of IFN signaling in both myeloid and tumor cells, and 4) reduced glioma-associated gene signature that predicts poor prognosis in glioma patients. This is the first study to establish a role for PP2A in regulating dsDNA-cGAS-STING signaling and collectively, our results suggest that PP2A is a promising novel target to enhance anti-tumor immunity for glioma.
2023-05-17 | GSE213307 | GEO
Project description:STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
2023-02-09 | GSE199251 | GEO
Project description:STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
2023-02-09 | GSE199247 | GEO