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Hayriye V. Erkizan - One of the best experts on this subject based on the ideXlab platform.
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Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.
Experimental Cell Research, 2012Co-Authors: Ogan D. Abaan, Wiljan Hendriks, Aykut Üren, Jeffrey A. Toretsky, Hayriye V. ErkizanAbstract:Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings Sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
Jeffrey A. Toretsky - One of the best experts on this subject based on the ideXlab platform.
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Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.
Experimental Cell Research, 2012Co-Authors: Ogan D. Abaan, Wiljan Hendriks, Aykut Üren, Jeffrey A. Toretsky, Hayriye V. ErkizanAbstract:Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings Sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
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Tumor expression of 4-1BB ligand sustains tumor lytic T cells.
Cancer Biology & Therapy, 2003Co-Authors: Hua Zhang, Melinda S. Merchant, Chand Khanna, Bill Telford, Yvona Ward, Jeffrey Summers, Kevin S Chua, Jeffrey A. Toretsky, Lee J Helman, Elaine K. ThomasAbstract:Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewings Sarcoma. Circulating T cells from patients with progressively growing Ewings tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28-/4-1BB+. Autologous Ewings tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Simislarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of...
Jacob G Scott - One of the best experts on this subject based on the ideXlab platform.
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abstract 6563 network potential identifies therapeutic mirna cocktails in Ewings Sarcoma
Cancer Research, 2020Co-Authors: Davis T Weaver, Kathleen I Pishas, Drew F K Williamson, Jessica A Scarborough, Stephen L Lessnick, Andrew Dhawan, Jacob G ScottAbstract:Introduction: Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field owing to their ability to repress multiple, predictable targets and cause widespread changes in a cell signaling network. New miRNA-based oligonucleotide drugs have have shown significant promise for the treatment of cancer in pre-clinical studies. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets. Methods: In this work, we present a novel network science-based approach for identification of potential miRNA therapies, using Ewings Sarcoma as a model system. We first characterized 6 Ewings cell lines using paired mRNA and miRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential, aiming to approximate the relative importance of each protein to network stability in decreasing the network potential. After identifying these mRNA targets, we sought to identify miRNAs and combinations of miRNAs that preferentially act to repress these targets, with the aim of defining synthetic miRNA-based therapy for down-regulation of these targets. Results: We identified TRIM25, APP, ELAV1, RNF4, XPO1 as ideal protein targets for therapy for each of the six cell lines based on the degree of network disruption induced when each gene was modeled as repressed. The expanded list of targets was enriched for genes involved in the canonical miRNA biogenesis pathway, suggesting a link between signaling network disruption and miRNA production. Using miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as the optimal miRNAs for preferential repression of these targets. Discussion: In this work, we applied a novel pipeline for identification of miRNAs candidates for cancer therapy. Using a measure of network state, network potential, we identified potential mRNA targets crucial to the stability of the Ewings Sarcoma signaling network, including known drivers of tumor progression and genes involved in miRNA biogenesis. Applying mRNA-miRNA mappings, we successfully identified miRNAs and combinations of miRNAs that, if introduced synthetically, are predicted to preferentially and dramatically disrupt the Ewings Sarcoma signaling network. Citation Format: Davis T. Weaver, Kathleen I. Pishas, Drew Williamson, Jessica Scarborough, Stephen L. Lessnick, Andrew Dhawan, Jacob G. Scott. Network potential identifies therapeutic miRNA cocktails in Ewings Sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6563.
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identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewings Sarcoma
bioRxiv, 2020Co-Authors: Jessica A Scarborough, Stephen L Lessnick, Andrew Dhawan, Erin Mcclure, Peter M Anderson, Arda Durmaz, Masahiro Hitomi, Jacob G ScottAbstract:Ewings Sarcoma (EWS) is the second most common primary malignant bone cancer in children. Advances in the treatment of EWS are desperately needed, particularly in the case of metastatic disease. A deeper understanding of collateral sensitivity, where the evolution of therapeutic resistance to one drug aligns with sensitivity to another drug, may improve our ability to effectively target this disease. For the first time in a solid tumor, we examine the repeatability of collateral sensitivity in EWS cell lines over time as evolutionary replicates evolve resistance to standard treatment. In doing so, we produced a temporal collateral sensitivity map that allows us to examine the evolution of collateral sensitivity and resistance in EWS. We found that the evolution of collateral sensitivity and resistance was predictable with some drugs, but had significant variation in response to other drugs. Samples that were most sensitive and most resistant to all drugs were compared using differential gene expression. Using this map of temporal collateral sensitivity in EWS, we can see that the path towards collateral sensitivity is not always repeatable, nor is there always a clear trajectory towards resistance or sensitivity. Identifying transcriptomic changes that accompany these states of transient collateral sensitivity could improve treatment planning for EWS patients.
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network potential identifies therapeutic mirna cocktails in Ewings Sarcoma
bioRxiv, 2019Co-Authors: Davis T Weaver, Kathleen I Pishas, Drew F K Williamson, Jessica A Scarborough, Stephen L Lessnick, Andrew Dhawan, Jacob G ScottAbstract:ABSTRACT Introduction Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field owing to their ability to repress multiple, predictable targets and cause widespread changes in a cell signaling network. New miRNA-based oligonucleotide drugs have have shown significant promise for the treatment of cancer in pre-clinical studies. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets. Methods In this work, we present a novel network science-based approach for identification of potential miRNA therapies, using Ewings Sarcoma as a model system. We first characterized 6 EW cell lines using paired mRNA and miRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential, aiming to approximate the relative importance of each protein to network stability in decreasing the network potential. After identifying these mRNA targets, we sought to identify miRNAs and combinations of miRNAs that preferentially act to repress these targets, with the aim of defining synthetic miRNA-based therapy for down-regulation of these targets. Results We identified TRIM25, APP, ELAV1, RNF4, XPO1 as ideal protein targets for therapy for each of the six cell lines based on the degree of network disruption induced when each gene was modeled as repressed. The expanded list of targets was enriched for genes involved in the canonical miRNA biogenesis pathway, suggesting a link between signaling network disruption and miRNA production. Using miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as the optimal miRNAs for preferential repression of these targets. Discussion In this work, we applied a novel pipeline for identification of miRNAs candidates for cancer therapy. Using a measure of network state, network potential, we identified potential mRNA targets crucial to the stability of the Ewings Sarcoma signaling network, including known drivers of tumor progression and genes involved in miRNA biogenesis. Applying mRNA-miRNA mappings, we successfully identified miRNAs and combinations of miRNAs that, if introduced synthetically, are predicted to preferentially and dramatically disrupt the Ewings Sarcoma signaling network.
Ogan D. Abaan - One of the best experts on this subject based on the ideXlab platform.
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Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.
Experimental Cell Research, 2012Co-Authors: Ogan D. Abaan, Wiljan Hendriks, Aykut Üren, Jeffrey A. Toretsky, Hayriye V. ErkizanAbstract:Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings Sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
Aykut Üren - One of the best experts on this subject based on the ideXlab platform.
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Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.
Experimental Cell Research, 2012Co-Authors: Ogan D. Abaan, Wiljan Hendriks, Aykut Üren, Jeffrey A. Toretsky, Hayriye V. ErkizanAbstract:Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings Sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
