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Article: PSPC1 potentiates TGF-β-dependent metastatic dissemination.

Yeh, Hsi-Wen / Jou, Yuh-Shan

Molecular & cellular oncology

2018 Volume 5, Issue 4, Page(s) e1472058

Abstract: Metastatic reprogramming toward malignant tumor progression relies on the activation of oncogenic regulators, yet the cellular determinants remain elucidated. Through identification of aberrant prognostic cancer genes, we identified paraspeckle component ...

Abstract	Metastatic reprogramming toward malignant tumor progression relies on the activation of oncogenic regulators, yet the cellular determinants remain elucidated. Through identification of aberrant prognostic cancer genes, we identified paraspeckle component 1 (PSPC1) functions as a master activator of metastatic reprogramming by activating epithelial-to-mesenchymal transition (EMT), stemness and TGF-β1 pro-metastatic switch.
Language	English
Publishing date	2018-08-01
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2018.1472058
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Article: Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

Unlu, Gokhan / Prizer, Benjamin / Erdal, Ranya / Yeh, Hsi-Wen / Bayraktar, Erol C. / Birsoy, Kıvanç

Molecular cell. 2022 Aug. 04, v. 82, no. 15

2022

Abstract: Iron is the most abundant transition metal essential for numerous cellular processes. Although most mammalian cells acquire iron through transferrin receptors, molecular players of iron utilization under iron restriction are incompletely understood. To ... ...

Abstract	Iron is the most abundant transition metal essential for numerous cellular processes. Although most mammalian cells acquire iron through transferrin receptors, molecular players of iron utilization under iron restriction are incompletely understood. To address this, we performed metabolism-focused CRISPRa gain-of-function screens, which revealed metabolic limitations under stress conditions. Iron restriction screens identified not only expected members of iron utilization pathways but also SLCO2B1, a poorly characterized membrane carrier. SLCO2B1 expression is sufficient to increase intracellular iron, bypass the essentiality of the transferrin receptor, and enable proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain, and primary Slco2b1⁻/⁻ mouse microglia exhibit strong defects in heme analog import. Altogether, our work identifies SLCO2B1 as a microglia-enriched plasma membrane heme importer and provides a genetic platform to identify metabolic limitations under stress conditions.
Keywords	brain ; gain-of-function mutation ; gene activation ; heme ; heme oxygenase (biliverdin-producing) ; iron ; mice ; neuroglia ; plasma membrane ; transferrin ; transferrin receptors
Language	English
Dates of publication	2022-0804
Size	p. 2832-2843.e7.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.05.024
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Article ; Online: Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.

Unlu, Gokhan / Prizer, Benjamin / Erdal, Ranya / Yeh, Hsi-Wen / Bayraktar, Erol C / Birsoy, Kıvanç

Molecular cell

2022 Volume 82, Issue 19, Page(s) 3750

Language	English
Publishing date	2022-10-08
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.09.004
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Article ; Online: Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.

Unlu, Gokhan / Prizer, Benjamin / Erdal, Ranya / Yeh, Hsi-Wen / Bayraktar, Erol C / Birsoy, Kıvanç

Molecular cell

2022 Volume 82, Issue 15, Page(s) 2832–2843.e7

Abstract	Iron is the most abundant transition metal essential for numerous cellular processes. Although most mammalian cells acquire iron through transferrin receptors, molecular players of iron utilization under iron restriction are incompletely understood. To address this, we performed metabolism-focused CRISPRa gain-of-function screens, which revealed metabolic limitations under stress conditions. Iron restriction screens identified not only expected members of iron utilization pathways but also SLCO2B1, a poorly characterized membrane carrier. SLCO2B1 expression is sufficient to increase intracellular iron, bypass the essentiality of the transferrin receptor, and enable proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain, and primary Slco2b1
MeSH term(s)	Animals ; Biological Transport ; Heme/genetics ; Heme/metabolism ; Iron/metabolism ; Mammals/metabolism ; Membrane Transport Proteins/metabolism ; Mice ; Organic Anion Transporters/metabolism ; Transcriptional Activation
Chemical Substances	Membrane Transport Proteins ; Organic Anion Transporters ; Slco2b1 protein, mouse ; Heme (42VZT0U6YR) ; Iron (E1UOL152H7)
Language	English
Publishing date	2022-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.05.024
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Article: A mouse model to study glutathione limitation

Timson, Rebecca C / Khan, Artem / Uygur, Beste / Saad, Marwa / Yeh, Hsi-Wen / DelGaudio, Nicole / Weber, Ross / Alwaseem, Hanan / Gao, Jing / Yang, Chingwen / Birsoy, Kıvanç

bioRxiv : the preprint server for biology

2024

Abstract: Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the ...

Abstract	Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.08.574722
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Article ; Online: Development of a mouse model expressing a bifunctional glutathione-synthesizing enzyme to study glutathione limitation in vivo.

Timson, Rebecca C / Khan, Artem / Uygur, Beste / Saad, Marwa / Yeh, Hsi-Wen / DelGaudio, Nicole L / Weber, Ross / Alwaseem, Hanan / Gao, Jing / Yang, Chingwen / Birsoy, Kıvanç

The Journal of biological chemistry

2024 Volume 300, Issue 2, Page(s) 105645

Abstract: Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer, and neurodegenerative disorders, ... ...

Abstract	Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer, and neurodegenerative disorders, studying the limiting role of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus thermophilus (GshF), which possesses both glutamate-cysteine ligase and glutathione synthase activities. GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis induction, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes further revealed genes required for cell proliferation under cellular and mitochondrial GSH depletion. Among these, we identified the glutamate-cysteine ligase modifier subunit, GCLM, as a requirement for cellular sensitivity to buthionine sulfoximine, a glutathione synthesis inhibitor. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the limiting role of GSH in physiology and disease.
MeSH term(s)	Animals ; Mice ; Buthionine Sulfoximine/pharmacology ; Disease Models, Animal ; Glutamate-Cysteine Ligase/genetics ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/metabolism ; Cell Line, Tumor ; Humans
Chemical Substances	Buthionine Sulfoximine (5072-26-4) ; Glutamate-Cysteine Ligase (EC 6.3.2.2) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.105645
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Article ; Online: A New Switch for TGFβ in Cancer.

Yeh, Hsi-Wen / Lee, Szu-Shuo / Chang, Chieh-Yu / Lang, Yaw-Dong / Jou, Yuh-Shan

Cancer research

2019 Volume 79, Issue 15, Page(s) 3797–3805

Abstract: The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late- ... ...

Abstract	The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFβ responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPβ, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFβ responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.
MeSH term(s)	Humans ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
Chemical Substances	Transforming Growth Factor beta
Language	English
Publishing date	2019-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-18-2019
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Article ; Online: Pyrimidine metabolic rate limiting enzymes in poorly-differentiated hepatocellular carcinoma are signature genes of cancer stemness and associated with poor prognosis.

Yeh, Hsi-Wen / Lee, Szu-Shuo / Chang, Chieh-Yu / Hu, Chun-Mei / Jou, Yuh-Shan

Oncotarget

2017 Volume 8, Issue 44, Page(s) 77734–77751

Abstract: Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to ... ...

Abstract	Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to uncover the aberrant expression of metabolic enzymes in poorly-differentiated human hepatocellular carcinoma (HCC) for revealing targets against HCC malignancy. A total of 135 upregulated (22 are rate-limiting enzymes (RLEs)) and 362 down-regulated (77 are RLEs) metabolic genes were identified and associated with poor patient survival in large-cohorts of HCC patients in TCGA-LIHC and two other independent transcriptomic studies. Ten out of 22 upregulated RLEs in poorly-differentiated HCC are critical enzymes in pyrimidine metabolism pathways in association with stemness features by gene enrichment analysis and upregulated in ALDH1
Language	English
Publishing date	2017-09-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.20774
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Article ; Online: SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells.

Wang, Ying / Yen, Frederick S / Zhu, Xiphias Ge / Timson, Rebecca C / Weber, Ross / Xing, Changrui / Liu, Yuyang / Allwein, Benjamin / Luo, Hanzhi / Yeh, Hsi-Wen / Heissel, Søren / Unlu, Gokhan / Gamazon, Eric R / Kharas, Michael G / Hite, Richard / Birsoy, Kıvanç

Nature

2021 Volume 599, Issue 7883, Page(s) 136–140

Abstract: Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative ... ...

Abstract	Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism
MeSH term(s)	Animals ; Biological Transport ; Cell Proliferation ; Cells, Cultured ; Erythropoiesis ; Glutathione/deficiency ; Glutathione/metabolism ; Homeostasis ; Humans ; Iron-Sulfur Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/genetics ; Mitochondrial Membrane Transport Proteins/metabolism ; Oxidation-Reduction ; Proteome ; Proteomics
Chemical Substances	Iron-Sulfur Proteins ; Mitochondrial Membrane Transport Proteins ; Proteome ; SLC25A39 protein, human ; SLC25A40 protein, human ; Slc25a39 protein, mouse ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2021-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-04025-w
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Article ; Online: PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression.

Lang, Yaw-Dong / Chen, Hsin-Yi / Ho, Chun-Ming / Shih, Jou-Ho / Hsu, En-Chi / Shen, Roger / Lee, Yu-Ching / Chen, Jyun-Wei / Wu, Cheng-Yen / Yeh, Hsi-Wen / Chen, Ruey-Hwa / Jou, Yuh-Shan

Nature communications

2019 Volume 10, Issue 1, Page(s) 5716

Abstract: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of ... ...

Abstract	Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.
MeSH term(s)	Adult ; Aged ; Animals ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/mortality ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Disease Progression ; Epithelial-Mesenchymal Transition/genetics ; Female ; Humans ; Kaplan-Meier Estimate ; Liver/pathology ; Liver Neoplasms/genetics ; Liver Neoplasms/mortality ; Liver Neoplasms/pathology ; Male ; Mice ; Middle Aged ; Mutation ; Neoplasm Proteins/metabolism ; Protein-Tyrosine Kinases/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Signal Transduction ; Up-Regulation ; Wnt3A Protein/metabolism ; Xenograft Model Antitumor Assays ; Young Adult ; beta Catenin/metabolism
Chemical Substances	CTNNB1 protein, human ; Neoplasm Proteins ; PSPC1 protein, human ; RNA-Binding Proteins ; WNT3A protein, human ; Wnt3A Protein ; beta Catenin ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; PTK6 protein, human (EC 2.7.10.2)
Language	English
Publishing date	2019-12-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-13665-6
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