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Article ; Online: Perturbation of Cellular Redox Homeostasis Dictates Divergent Effects of Polybutyl Cyanoacrylate (PBCA) Nanoparticles on Autophagy.

Sønstevold, Tonje / Engedal, Nikolai / Torgersen, Maria Lyngaas

2021 Volume 10, Issue 12

Abstract: Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly( ... ...

Abstract	Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly(butyl cyanoacrylate) (PBCA) perturbs redox homeostasis in human epithelial cells, and that the degree of redox perturbation dictates divergent effects of PBCA on autophagy. Specifically, PBCA promoted functional autophagy at low concentrations, whereas it inhibited autophagy at high concentrations. Both effects were completely abolished by the antioxidant N-acetyl cysteine (NAC). High concentrations of PBCA inhibited MAP1LC3B/GABARAP lipidation and LC3 flux, and blocked bulk autophagic cargo flux induced by mTOR inhibition. These effects were mimicked by the redox regulator H
MeSH term(s)	Acetylcysteine/metabolism ; Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Antioxidants/pharmacology ; Autophagy/drug effects ; Autophagy/genetics ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Proteins/genetics ; Beclin-1/genetics ; Class III Phosphatidylinositol 3-Kinases/genetics ; Drug Delivery Systems ; Enbucrilate/chemistry ; Enbucrilate/pharmacology ; Epithelial Cells/drug effects ; Gene Expression Regulation/drug effects ; Homeostasis/drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Hydrogen Peroxide/pharmacology ; MAP Kinase Kinase 4/genetics ; Nanoparticles/chemistry ; Oxidation-Reduction/drug effects ; p38 Mitogen-Activated Protein Kinases/genetics
Chemical Substances	ATG13 protein, human ; Antioxidants ; Autophagy-Related Proteins ; Beclin-1 ; Hydrogen Peroxide (BBX060AN9V) ; Class III Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; Enbucrilate (F8CEP82QNP) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10123432
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Article ; Online: ATPase activity of DFCP1 controls selective autophagy.

Nähse, Viola / Raiborg, Camilla / Tan, Kia Wee / Mørk, Sissel / Torgersen, Maria Lyngaas / Wenzel, Eva Maria / Nager, Mireia / Salo, Veijo T / Johansen, Terje / Ikonen, Elina / Schink, Kay Oliver / Stenmark, Harald

Nature communications

2023 Volume 14, Issue 1, Page(s) 4051

Abstract: Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) ...

Abstract	Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) known as omegasomes, which are characterized by the presence of the ER protein DFCP1/ZFYVE1. The function of DFCP1 is unknown, as are the mechanisms of omegasome formation and constriction. Here, we demonstrate that DFCP1 is an ATPase that is activated by membrane binding and dimerizes in an ATP-dependent fashion. Whereas depletion of DFCP1 has a minor effect on bulk autophagic flux, DFCP1 is required to maintain the autophagic flux of p62 under both fed and starved conditions, and this is dependent on its ability to bind and hydrolyse ATP. While DFCP1 mutants defective in ATP binding or hydrolysis localize to forming omegasomes, these omegasomes fail to constrict properly in a size-dependent manner. Consequently, the release of nascent autophagosomes from large omegasomes is markedly delayed. While knockout of DFCP1 does not affect bulk autophagy, it inhibits selective autophagy, including aggrephagy, mitophagy and micronucleophagy. We conclude that DFCP1 mediates ATPase-driven constriction of large omegasomes to release autophagosomes for selective autophagy.
MeSH term(s)	Macroautophagy ; Autophagy/genetics ; Endoplasmic Reticulum/metabolism ; Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism
Chemical Substances	Adenosine Triphosphatases (EC 3.6.1.-) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2023-07-08
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/s41467-023-39641-9
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Article ; Online: TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy.

Kaur, Namrita / de la Ballina, Laura Rodriguez / Haukaas, Håvard Styrkestad / Torgersen, Maria Lyngaas / Radulovic, Maja / Munson, Michael J / Sabirsh, Alan / Stenmark, Harald / Simonsen, Anne / Carlsson, Sven R / Lystad, Alf Håkon

The EMBO journal

2023 Volume 42, Issue 17, Page(s) e113105

Abstract: Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin-like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM ... ...

Abstract	Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin-like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes to sense membrane damage, but so far, only the mechanism to activate ATG16L1-containing E3 complexes, associated with proton gradient loss, has been described. Here, we show that TECPR1-containing E3 complexes are key mediators of CASM in cells treated with a variety of pharmacological drugs, including clinically relevant nanoparticles, transfection reagents, antihistamines, lysosomotropic compounds, and detergents. Interestingly, TECPR1 retains E3 activity when ATG16L1 CASM activity is obstructed by the Salmonella Typhimurium pathogenicity factor SopF. Mechanistically, TECPR1 is recruited by damage-induced sphingomyelin (SM) exposure using two DysF domains, resulting in its activation and ATG8 lipidation. In vitro assays using purified human TECPR1-ATG5-ATG12 complex show direct activation of its E3 activity by SM, whereas SM has no effect on ATG16L1-ATG5-ATG12. We conclude that TECPR1 is a key activator of CASM downstream of SM exposure.
MeSH term(s)	Humans ; Autophagy-Related Protein 5/metabolism ; Sphingomyelins ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Ubiquitins ; Autophagy ; Microtubule-Associated Proteins/metabolism ; Autophagy-Related Protein 12/metabolism ; Membrane Proteins/metabolism
Chemical Substances	Autophagy-Related Protein 5 ; Sphingomyelins ; Autophagy-Related Proteins ; Ubiquitins ; Microtubule-Associated Proteins ; Autophagy-Related Protein 12 ; TECPR1 protein, human ; Membrane Proteins
Language	English
Publishing date	2023-07-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2022113105
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Article ; Online: Cabazitaxel-loaded poly(alkyl cyanoacrylate) nanoparticles: toxicity and changes in the proteome of breast, colon and prostate cancer cells.

Øverbye, Anders / Torgersen, Maria Lyngaas / Sønstevold, Tonje / Iversen, Tore Geir / Mørch, Ýrr / Skotland, Tore / Sandvig, Kirsten

Nanotoxicology

2021 Volume 15, Issue 7, Page(s) 865–884

Abstract: Nanoparticles composed of poly(alkyl cyanoacrylate) (PACA) have shown great promise due to their biodegradability and high drug loading capacity. Development of optimal PACA nanocarriers requires detailed analysis of the overall cellular impact exerted ... ...

Abstract	Nanoparticles composed of poly(alkyl cyanoacrylate) (PACA) have shown great promise due to their biodegradability and high drug loading capacity. Development of optimal PACA nanocarriers requires detailed analysis of the overall cellular impact exerted by PACA variants. We here perform a comprehensive comparison of cabazitaxel (CBZ)-loaded nanocarriers composed of three different PACA monomers, i.e. poly(n-butyl cyanoacrylate) (PBCA), poly(2-ethylbutyl cyanoacrylate) (PEBCA) and poly(octyl cyanoacrylate) (POCA). The cytotoxicity of drug-loaded and empty PACA nanoparticles were compared to that of free CBZ across a panel of nine cancer cell lines by assessing cellular metabolism, proliferation and protein synthesis. The analyses revealed that the cytotoxicity of all CBZ-loaded PACAs was similar to that of free CBZ for all cell lines tested, whereas the empty PACAs exerted much lower toxicity. To increase our understanding of the toxic effects of these treatments comprehensive MS-based proteomics were performed with HCT116, MDA-MB-231 and PC3 cells incubated with PACA-CBZ variants or free CBZ. Interestingly, PACA-CBZ specifically led to decreased levels of proteins involved in focal adhesion and stress fibers in all cell lines. Since we recently demonstrated that encapsulation of CBZ within PEBCA nanoparticles significantly improved the therapeutic effect of CBZ on a patient derived xenograft model in mice, we investigated the effects of this PACA variant more closely by immunoblotting. Interestingly, we detected several changes in the protein expression and degree of phosphorylation of SRC-pathway proteins that can be relevant for the therapeutic effects of these substances.
MeSH term(s)	Animals ; Colon ; Cyanoacrylates/therapeutic use ; Cyanoacrylates/toxicity ; Drug Carriers ; Humans ; Male ; Mice ; Nanoparticles/toxicity ; Prostatic Neoplasms/drug therapy ; Proteome ; Taxoids
Chemical Substances	Cyanoacrylates ; Drug Carriers ; Proteome ; Taxoids ; cabazitaxel (51F690397J)
Language	English
Publishing date	2021-05-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2237988-5
ISSN	1743-5404 ; 1743-5390
ISSN (online)	1743-5404
ISSN	1743-5390
DOI	10.1080/17435390.2021.1924888
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Article ; Online: Autophagy: friend or foe in the treatment of fusion protein-associated leukemias?

Torgersen, Maria Lyngaas / Simonsen, Anne

Autophagy

2013 Volume 9, Issue 12, Page(s) 2175–2177

Abstract: Both radiation and chemotherapeutic drugs induce autophagy in tumor cells, and whether this contributes to cell death or survival is debated. Although a prodeath role has been reported in certain contexts, treatment-induced autophagy often exerts a ... ...

Abstract	Both radiation and chemotherapeutic drugs induce autophagy in tumor cells, and whether this contributes to cell death or survival is debated. Although a prodeath role has been reported in certain contexts, treatment-induced autophagy often exerts a prosurvival function by preventing apoptosis and delaying necrosis. Interestingly, a more specific role of autophagy has been demonstrated in certain subtypes of leukemia. The fusion oncoproteins PML-RARA and BCR-ABL, the main oncogenic drivers of acute promyelocytic leukemia and chronic myeloid leukemia (CML), respectively, have recently been identified as autophagy substrates and their degradation by autophagy shown to contribute to treatment. However, this does not seem to be a general feature of leukemic fusion oncoproteins, as we recently found that AML1-ETO, the most frequently occurring acute myeloid leukemia (AML) fusion protein, is not an autophagy substrate. Rather we demonstrate a clear prosurvival role of autophagy in this AML subtype and that addition of autophagy inhibitors in the treatment regimen might be beneficial.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Autophagy/drug effects ; Autophagy/physiology ; Cell Survival/genetics ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/metabolism ; Drug Resistance, Neoplasm/genetics ; Fusion Proteins, bcr-abl/genetics ; Fusion Proteins, bcr-abl/metabolism ; Histone Deacetylase Inhibitors/administration & dosage ; Humans ; Leukemia/genetics ; Leukemia/pathology ; Leukemia/therapy ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; RUNX1 Translocation Partner 1 Protein
Chemical Substances	AML1-ETO fusion protein, human ; Core Binding Factor Alpha 2 Subunit ; Histone Deacetylase Inhibitors ; Oncogene Proteins, Fusion ; RUNX1 Translocation Partner 1 Protein ; promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein ; Fusion Proteins, bcr-abl (EC 2.7.10.2)
Language	English
Publishing date	2013-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.26559
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Article ; Online: A novel SARS-CoV-2 Beta RBD DNA vaccine directly targeted to antigen-presenting cells induces strong humoral and T cell responses.

Kuczkowska, Katarzyna / Bjerkan, Louise / Stubsrud, Elisabeth / Husbyn, Hannah Cuthbertson / Chellappa, Stalin / Hauge, Anette / Skarshaug, Renate / Torgersen, Maria Lyngaas / Heim, Joel Benjamin / Jørgensen, Marthe Jøntvedt / Wold, Christian Winther / Schleimann, Mariane Høgsbjerg / Tolstrup, Martin / Granum, Stine / Fredriksen, Agnete Brunsvik / Pedersen, Mikkel Wandahl / Norheim, Gunnstein

Scientific reports

2023 Volume 13, Issue 1, Page(s) 18902

Abstract: Throughout the COVID-19 pandemic, several variants of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have evolved, affecting the efficacy of the approved COVID-19 vaccines. To address the need for vaccines that induce ... ...

Abstract	Throughout the COVID-19 pandemic, several variants of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have evolved, affecting the efficacy of the approved COVID-19 vaccines. To address the need for vaccines that induce strong and persistent cross-reactive neutralizing antibodies and T cell responses, we developed a prophylactic SARS-CoV-2 vaccine candidate based on our easily and rapidly adaptable plasmid DNA vaccine platform. The vaccine candidate, referred to here as VB2129, encodes a protein homodimer consisting of the receptor binding domain (RBD) from lineage B.1.351 (Beta) of SARS-CoV-2, a VoC with a severe immune profile, linked to a targeting unit (human LD78β/CCL3L1) that binds chemokine receptors on antigen-presenting cells (APCs) and a dimerization unit (derived from the hinge and C
MeSH term(s)	Animals ; Humans ; Mice ; COVID-19 Vaccines ; SARS-CoV-2 ; Vaccines, DNA ; Pandemics ; COVID-19/prevention & control ; T-Lymphocytes ; Antigen-Presenting Cells ; Cancer Vaccines ; Broadly Neutralizing Antibodies ; DNA ; Immunoglobulin G ; Antibodies, Neutralizing ; Antibodies, Viral
Chemical Substances	COVID-19 Vaccines ; Vaccines, DNA ; Cancer Vaccines ; Broadly Neutralizing Antibodies ; DNA (9007-49-2) ; Immunoglobulin G ; Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2023-11-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-46223-8
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Article ; Online: Biological response and cytotoxicity induced by lipid nanocapsules.

Szwed, Marzena / Torgersen, Maria Lyngaas / Kumari, Remya Valsala / Yadava, Sunil Kumar / Pust, Sascha / Iversen, Tore Geir / Skotland, Tore / Giri, Jyotsnendu / Sandvig, Kirsten

Journal of nanobiotechnology

2020 Volume 18, Issue 1, Page(s) 5

Abstract: Background: Lipid nanocapsules (LNCs) are promising vehicles for drug delivery. However, since not much was known about cellular toxicity of these nanoparticles in themselves, we have here investigated the mechanisms involved in LNC-induced intoxication ...

Abstract	Background: Lipid nanocapsules (LNCs) are promising vehicles for drug delivery. However, since not much was known about cellular toxicity of these nanoparticles in themselves, we have here investigated the mechanisms involved in LNC-induced intoxication of the three breast cancer cell lines MCF-7, MDA-MD-231 and MDA-MB-468. The LNCs used were made of Labrafac™ Lipophile WL1349, Lipoid Results: High resolution SIM microscopy showed that the DiD-labeled LNCs ended up in lysosomes close to the membrane. Empty LNCs, i.e. without encapsulated drug, induced not only increased lysosomal pH, but also acidification of the cytosol and a rapid inhibition of protein synthesis. The cytotoxicity of the LNCs were measured for up to 72 h of incubation using the MTT assay and ATP measurements in all three cell lines, and revealed that MDA-MB-468 was the most sensitive cell line and MCF-7 the least sensitive cell line to these LNCs. The LNCs induced generation of reactive free oxygen species and lipid peroxidation. Experiments with knock-down of kinases in the near-haploid cell line HAP1 indicated that the kinase HRI is essential for the observed phosphorylation of eIF2α. Nrf2 and ATF4 seem to play a protective role against the LNCs in MDA-MB-231 cells, as knock-down of these factors sensitizes the cells to the LNCs. This is in contrast to MCF-7 cells where the knock-down of these factors had a minor effect on the toxicity of the LNCs. Inhibitors of ferroptosis provided a large protection against LNC toxicity in MDA-MB-231 cells, but not in MCF-7 cells. Conclusions: High doses of LNCs showed a different degree of toxicity on the three cell lines studied, i.e. MCF-7, MDA-MD-231 and MDA-MB-468 and affected signaling factors and the cell fate differently in these cell lines.
MeSH term(s)	Activating Transcription Factor 4/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Endocytosis/drug effects ; Ferroptosis/drug effects ; Homeostasis/drug effects ; Humans ; Hydrogen-Ion Concentration ; Lipids/toxicity ; Lysosomes/drug effects ; Lysosomes/metabolism ; NF-E2-Related Factor 2/metabolism ; Nanocapsules/toxicity ; Nanocapsules/ultrastructure ; Oxidation-Reduction ; Protein Biosynthesis/drug effects ; Reactive Oxygen Species/metabolism ; Stress, Physiological/drug effects
Chemical Substances	ATF4 protein, human ; Lipids ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Nanocapsules ; Reactive Oxygen Species ; Activating Transcription Factor 4 (145891-90-3)
Language	English
Publishing date	2020-01-06
Publishing country	England
Document type	Journal Article
ISSN	1477-3155
ISSN (online)	1477-3155
DOI	10.1186/s12951-019-0567-y
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Article ; Online: Publisher Correction: Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy.

SenGupta, Tanima / Torgersen, Maria Lyngaas / Kassahun, Henok / Vellai, Tibor / Simonsen, Anne / Nilsen, Hilde

Nature communications

2018 Volume 9, Page(s) 16206

Abstract: This corrects the article DOI: 10.1038/ncomms3674. ...

Abstract	This corrects the article DOI: 10.1038/ncomms3674.
Language	English
Publishing date	2018-03-29
Publishing country	England
Document type	Journal Article ; Published Erratum
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/ncomms16206
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Article ; Online: Cell-penetrating peptides: possibilities and challenges for drug delivery in vitro and in vivo.

Skotland, Tore / Iversen, Tore Geir / Torgersen, Maria Lyngaas / Sandvig, Kirsten

Molecules (Basel, Switzerland)

2015 Volume 20, Issue 7, Page(s) 13313–13323

Abstract: In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface ... ...

Abstract	In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface and subsequently endocytosed or actually transported into the cytosol, either by direct plasma membrane penetration or after endocytosis. This discussion includes comments about pitfalls when using pharmacological inhibitors in such studies. The possibility of exploiting CPPs as carriers for the delivery of drugs of different sizes in vitro is discussed, as is the use of CPPs as carriers for therapeutic drugs or contrast agents in vivo. We conclude that in many cases, more studies are needed to demonstrate conclusively whether increased delivery of a substance attached to CPPs is due to a membrane-penetrating property or whether the increase is a consequence of just changing the charge of the substance to be delivered. Finally, the expected dose needed for the use of such conjugates in vivo is discussed, including aspects to consider in order to bring potential products into clinical use.
MeSH term(s)	Animals ; Biological Transport, Active ; Cell Membrane/metabolism ; Cell-Penetrating Peptides/chemistry ; Cell-Penetrating Peptides/pharmacokinetics ; Cell-Penetrating Peptides/pharmacology ; Drug Delivery Systems/methods ; Endocytosis/drug effects ; Humans
Chemical Substances	Cell-Penetrating Peptides
Language	English
Publishing date	2015-07-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules200713313
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Article ; Online: The kinase PERK and the transcription factor ATF4 play distinct and essential roles in autophagy resulting from tunicamycin-induced ER stress.

Luhr, Morten / Torgersen, Maria Lyngaas / Szalai, Paula / Hashim, Adnan / Brech, Andreas / Staerk, Judith / Engedal, Nikolai

The Journal of biological chemistry

2019 Volume 294, Issue 20, Page(s) 8197–8217

Abstract: Endoplasmic reticulum (ER) stress is thought to activate autophagy via unfolded protein response (UPR)-mediated transcriptional up-regulation of autophagy machinery components and modulation of microtubule-associated protein 1 light chain 3 (LC3). The ... ...

Abstract	Endoplasmic reticulum (ER) stress is thought to activate autophagy via unfolded protein response (UPR)-mediated transcriptional up-regulation of autophagy machinery components and modulation of microtubule-associated protein 1 light chain 3 (LC3). The upstream UPR constituents pancreatic EIF2-α kinase (PERK) and inositol-requiring enzyme 1 (IRE1) have been reported to mediate these effects, suggesting that UPR may stimulate autophagy via PERK and IRE1. However, how the UPR and its components affect autophagic activity has not been thoroughly examined. By analyzing the flux of LC3 through the autophagic pathway, as well as the sequestration and degradation of autophagic cargo, we here conclusively show that the classical ER stressor tunicamycin (TM) enhances autophagic activity in mammalian cells. PERK and its downstream factor, activating transcription factor 4 (ATF4), were crucial for this induction, but surprisingly, IRE1 constitutively suppressed autophagic activity. TM-induced autophagy required autophagy-related 13 (ATG13), Unc-51-like autophagy-activating kinases 1/2 (ULK1/ULK2), and GABA type A receptor-associated proteins (GABARAPs), but interestingly, LC3 proteins appeared to be redundant. Strikingly, ATF4 was activated independently of PERK in both LNCaP and HeLa cells, and our further examination revealed that ATF4 and PERK regulated autophagy through separate mechanisms. Specifically, whereas ATF4 controlled transcription and was essential for autophagosome formation, PERK acted in a transcription-independent manner and was required at a post-sequestration step in the autophagic pathway. In conclusion, our results indicate that TM-induced UPR activates functional autophagy, and whereas IRE1 is a negative regulator, PERK and ATF4 are required at distinct steps in the autophagic pathway.
MeSH term(s)	Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism ; Autophagic Cell Death/drug effects ; Autophagic Cell Death/genetics ; Autophagosomes/metabolism ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/genetics ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; PC-3 Cells ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Transcription, Genetic/drug effects ; Transcription, Genetic/genetics ; Tunicamycin/pharmacology ; Unfolded Protein Response/drug effects ; Unfolded Protein Response/genetics ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	ATF4 protein, human ; ATG13 protein, human ; Autophagy-Related Proteins ; Intracellular Signaling Peptides and Proteins ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Tunicamycin (11089-65-9) ; Activating Transcription Factor 4 (145891-90-3) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; EIF2AK3 protein, human (EC 2.7.11.1) ; ERN1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1) ; Ulk2 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2019-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA118.002829
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