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Article ; Online: Large tumour-derived extracellular vesicles as prognostic indicators of metastatic cancer patient survival.

Goberdhan, Deborah C I

2022 Volume 128, Issue 3, Page(s) 471–473

Abstract: Extracellular vesicles (EVs) are released by all cells and produced at particularly high levels by many cancer cells, often inducing pro-tumorigenic effects. Since these cancer EVs carry tumour proteins and RNAs, they can potentially be used at ... ...

Abstract	Extracellular vesicles (EVs) are released by all cells and produced at particularly high levels by many cancer cells, often inducing pro-tumorigenic effects. Since these cancer EVs carry tumour proteins and RNAs, they can potentially be used at biomarkers. The heterogeneity of surface markers and cargos carried by EVs, however, presents some challenges to developing such approaches. Nanou et al. [1] found that automated counting of large tumour-derived EVs (tdEVs) performed at least as effectively as counting circulating tumour-derived cells (CTCs) and with higher sensitivity, in distinguishing the survival of patients with castration-resistant prostate cancer (CRPC), metastatic colorectal cancer (mCRC) and metastatic breast cancer (MBC), but not for non-small cell lung cancer (NSCLC). Subsequent work has suggested that these tdEVs may also be used to assess tumour subtype and that the number of large EVs produced by endothelial cells can also be increased in cancer patients. While by itself, the tdEV imaging approach used by Nanou et al. [1] is not specific enough to predict the survival of individual patients, in combination with other EV-associated assays, this test, perhaps enhanced through the inclusion of other tumour antigens, could prove invaluable in predicting cancer survival and other outcomes in the clinic.
MeSH term(s)	Male ; Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Prognosis ; Endothelial Cells/pathology ; Lung Neoplasms/pathology ; Extracellular Vesicles/metabolism ; Neoplastic Cells, Circulating/pathology ; Neoplasms, Second Primary/pathology
Language	English
Publishing date	2022-11-16
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-02055-3
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Article ; Online: MISEV2023: An updated guide to EV research and applications.

Welsh, Joshua A / Goberdhan, Deborah C / O'Driscoll, Lorraine / Théry, Clotilde / Witwer, Kenneth W

Journal of extracellular vesicles

2024 Volume 13, Issue 2, Page(s) e12416

Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Editorial
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12416
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Article: PATs and SNATs: Amino Acid Sensors in Disguise.

Fan, Shih-Jung / Goberdhan, Deborah C I

Frontiers in pharmacology

2018 Volume 9, Page(s) 640

Abstract: Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to ... ...

Abstract	Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought in to cells by a wide range of SLCs including the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) and Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) families. More than a decade ago, the first evidence emerged that members of the PAT family can act as amino acid-stimulated receptors, or so-called "transceptors," connecting amino acids to mTORC1 activation. Since then, further studies in human cell models have suggested that other PAT and SNAT family members, which share significant homology within their transmembrane domains, can act as transceptors. A paradigm shift has also led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mTORC1. Much focus has been on late endosomes and lysosomes as mTORC1 regulatory hubs, but more recently a Golgi-localized PAT was shown to be required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity. These emerging features of PAT and SNAT amino acid sensors, including the transceptor mechanism, have implications for the pharmacological inhibition of mTORC1 and new therapeutic interventions.
Language	English
Publishing date	2018-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2018.00640
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Article ; Online: Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation.

Marie, Pauline P / Fan, Shih-Jung / Mason, John / Wells, Adam / Mendes, Cláudia C / Wainwright, S Mark / Scott, Sheherezade / Fischer, Roman / Harris, Adrian L / Wilson, Clive / Goberdhan, Deborah C I

Journal of extracellular vesicles

2023 Volume 12, Issue 3, Page(s) e12311

Abstract: Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7-positive multivesicular endosomes, and also in recycling Rab11a-positive endosomes, particularly under some forms of ...

Abstract	Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7-positive multivesicular endosomes, and also in recycling Rab11a-positive endosomes, particularly under some forms of nutrient stress. The core proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) participate in exosome biogenesis and ILV-mediated destruction of ubiquitinylated cargos. Accessory ESCRT-III components have reported roles in ESCRT-III-mediated vesicle scission, but their precise functions are poorly defined. They frequently only appear essential under stress. Comparative proteomics analysis of human small extracellular vesicles revealed that accessory ESCRT-III proteins, CHMP1A, CHMP1B, CHMP5 and IST1, are increased in Rab11a-enriched exosome preparations. We show that these proteins are required to form ILVs in Drosophila secondary cell recycling endosomes, but unlike core ESCRTs, they are not involved in degradation of ubiquitinylated proteins in late endosomes. Furthermore, CHMP5 knockdown in human HCT116 colorectal cancer cells selectively inhibits Rab11a-exosome production. Accessory ESCRT-III knockdown suppresses seminal fluid-mediated reproductive signalling by secondary cells and the growth-promoting activity of Rab11a-exosome-containing EVs from HCT116 cells. We conclude that accessory ESCRT-III components have a specific, ubiquitin-independent role in Rab11a-exosome generation, a mechanism that might be targeted to selectively block pro-tumorigenic activities of these vesicles in cancer.
MeSH term(s)	Humans ; Exosomes ; Extracellular Vesicles ; Endosomes ; Biological Transport ; Endosomal Sorting Complexes Required for Transport
Chemical Substances	Endosomal Sorting Complexes Required for Transport
Language	English
Publishing date	2023-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12311
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Article ; Online: Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells.

Sekar, Aashika / Leiblich, Aaron / Wainwright, S Mark / Mendes, Cláudia C / Sarma, Dhruv / Hellberg, Josephine E E U / Gandy, Carina / Goberdhan, Deborah C I / Hamdy, Freddie C / Wilson, Clive

PLoS genetics

2023 Volume 19, Issue 6, Page(s) e1010815

Abstract: In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of ...

Abstract	In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.
MeSH term(s)	Humans ; Animals ; Female ; Male ; Drosophila/metabolism ; Drosophila melanogaster/metabolism ; Prostate/pathology ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Prostatic Neoplasms, Castration-Resistant/pathology ; Endoreduplication ; Ecdysone/genetics ; Ecdysone/metabolism ; E2F1 Transcription Factor/genetics ; Transcription Factors/genetics ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism
Chemical Substances	ecdysone receptor ; Ecdysone (3604-87-3) ; E2F1 protein, human ; E2F1 Transcription Factor ; Rbf protein, Drosophila ; Transcription Factors ; Retinoblastoma Protein ; Drosophila Proteins
Language	English
Publishing date	2023-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010815
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Article ; Online: A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells.

Wells, Adam / Mendes, Cláudia C / Castellanos, Felix / Mountain, Phoebe / Wright, Tia / Wainwright, S Mark / Stefana, M Irina / Harris, Adrian L / Goberdhan, Deborah C I / Wilson, Clive

PLoS genetics

2023 Volume 19, Issue 10, Page(s) e1010979

Abstract: Secretory cells in glands and the nervous system frequently package and store proteins destined for regulated secretion in dense-core granules (DCGs), which disperse when released from the cell surface. Despite the relevance of this dynamic process to ... ...

Abstract	Secretory cells in glands and the nervous system frequently package and store proteins destined for regulated secretion in dense-core granules (DCGs), which disperse when released from the cell surface. Despite the relevance of this dynamic process to diseases such as diabetes and human neurodegenerative disorders, our mechanistic understanding is relatively limited, because of the lack of good cell models to follow the nanoscale events involved. Here, we employ the prostate-like secondary cells (SCs) of the Drosophila male accessory gland to dissect the cell biology and genetics of DCG biogenesis. These cells contain unusually enlarged DCGs, which are assembled in compartments that also form secreted nanovesicles called exosomes. We demonstrate that known conserved regulators of DCG biogenesis, including the small G-protein Arf1 and the coatomer complex AP-1, play key roles in making SC DCGs. Using real-time imaging, we find that the aggregation events driving DCG biogenesis are accompanied by a change in the membrane-associated small Rab GTPases which are major regulators of membrane and protein trafficking in the secretory and endosomal systems. Indeed, a transition from trans-Golgi Rab6 to recycling endosomal protein Rab11, which requires conserved DCG regulators like AP-1, is essential for DCG and exosome biogenesis. Our data allow us to develop a model for DCG biogenesis that brings together several previously disparate observations concerning this process and highlights the importance of communication between the secretory and endosomal systems in controlling regulated secretion.
MeSH term(s)	Animals ; Humans ; Male ; Dense Core Vesicles ; Drosophila ; Drosophila Proteins/genetics ; Exosomes/genetics ; Proteins ; rab GTP-Binding Proteins/genetics ; Transcription Factor AP-1
Chemical Substances	Drosophila Proteins ; Proteins ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Rab11 protein, Drosophila (EC 3.6.1.-) ; Transcription Factor AP-1 ; Rab6 protein, Drosophila (EC 3.6.1.-)
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010979
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Article: mTORC1 signalling mediates PI3K-dependent large lipid droplet accumulation in

Mensah, Lawrence B / Goberdhan, Deborah C I / Wilson, Clive

Biology open

2017 Volume 6, Issue 5, Page(s) 563–570

Abstract: Insulin and insulin-like growth factor signalling (IIS), which is primarily mediated by the PI3-kinase (PI3K)/PTEN/Akt kinase signalling cassette, is a highly evolutionarily conserved pathway involved in co-ordinating growth, development, ageing and ... ...

Abstract	Insulin and insulin-like growth factor signalling (IIS), which is primarily mediated by the PI3-kinase (PI3K)/PTEN/Akt kinase signalling cassette, is a highly evolutionarily conserved pathway involved in co-ordinating growth, development, ageing and nutrient homeostasis with dietary intake. It controls transcriptional regulators, in addition to promoting signalling by mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which stimulates biosynthesis of proteins and other macromolecules, and drives organismal growth. Previous studies in nutrient-storing germline nurse cells of the
Language	English
Publishing date	2017-05-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2632264-X
ISSN	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.022210
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Article ; Online: Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot.

Goberdhan, Deborah C I / Wilson, Clive / Harris, Adrian L

Cell metabolism

2016 Volume 23, Issue 4, Page(s) 580–589

Abstract: Cell metabolism and growth are matched to nutrient availability via the amino-acid-regulated mechanistic target of rapamycin complex 1 (mTORC1). Transporters have emerged as important amino acid sensors controlling mTOR recruitment and activation at the ... ...

Abstract	Cell metabolism and growth are matched to nutrient availability via the amino-acid-regulated mechanistic target of rapamycin complex 1 (mTORC1). Transporters have emerged as important amino acid sensors controlling mTOR recruitment and activation at the surface of multiple intracellular compartments. Classically, this has involved late endosomes and lysosomes, but now, in a recent twist, also the Golgi apparatus. Here we propose a model in which specific amino acids in assorted compartments activate different mTORC1 complexes, which may have distinct drug sensitivities and functions. We will discuss the implications of this for mTORC1 function in health and disease.
MeSH term(s)	Amino Acid Transport Systems/metabolism ; Amino Acids/metabolism ; Animals ; Biological Transport ; Endosomes/metabolism ; Golgi Apparatus/metabolism ; Humans ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Amino Acid Transport Systems ; Amino Acids ; Multiprotein Complexes ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2016-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2016.03.013
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Article ; Online: Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target?

Goberdhan, Deborah C I

Current opinion in investigational drugs (London, England : 2000)

2010 Volume 11, Issue 12, Page(s) 1360–1367

Abstract: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a multicomponent, nutrient-sensitive protein that is implicated in a wide range of major human diseases. mTORC1 responds to both growth factors and changes in local amino acid levels. Until ... ...

Abstract	Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a multicomponent, nutrient-sensitive protein that is implicated in a wide range of major human diseases. mTORC1 responds to both growth factors and changes in local amino acid levels. Until recently, the intracellular amino acid-sensing mechanism that regulates mTORC1 had remained unexplored. However, studies in human cells in culture have demonstrated that in response to amino acid stimulation, mTOR (a conserved member of the PI3K superfamily) is shuttled to late endosomal and lysosomal compartments, where it binds the Ragulator-Rag complex and is assembled into active mTORC1. Members of the proton-assisted amino acid transporter (PAT/SLC36) family have been identified as critical components of the amino acid-sensing system that regulates mTORC1 present in endosomal and lysosomal membranes. These discoveries not only highlight several new potential drug targets that could impact selectively on mTORC1 activity in cancer cells, but also provide novel insights into the strategies used by such cells to outcompete their neighbors in growth factor- and nutrient-depleted conditions. In this review, recent mechanistic insights into how mTORC1 activity is controlled by amino acids and the potential for the selective targeting this regulatory input are discussed.
MeSH term(s)	Amino Acid Transport Systems/metabolism ; Amino Acids/metabolism ; Animals ; Cytoplasm/metabolism ; Diptera/genetics ; Humans ; Intracellular Membranes/metabolism ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes ; Neoplasms/drug therapy ; Nutritional Physiological Phenomena ; Protein Binding ; Proteins/metabolism ; Signal Transduction ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases
Chemical Substances	Amino Acid Transport Systems ; Amino Acids ; Multiprotein Complexes ; Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2010-12-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2027913-9
ISSN	2040-3429 ; 0967-8298 ; 1472-4472
ISSN (online)	2040-3429
ISSN	0967-8298 ; 1472-4472
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Article ; Online: Author Correction: GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.

Dar, Ghulam Hassan / Mendes, Cláudia C / Kuan, Wei-Li / Speciale, Alfina A / Conceição, Mariana / Görgens, André / Uliyakina, Inna / Lobo, Miguel J / Lim, Wooi F / El Andaloussi, Samir / Mäger, Imre / Roberts, Thomas C / Barker, Roger A / Goberdhan, Deborah C I / Wilson, Clive / Wood, Matthew J A

Nature communications

2021 Volume 12, Issue 1, Page(s) 7357

Language	English
Publishing date	2021-12-16
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-27700-y
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