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Article ; Online: Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors.

Csibi, Alfredo / Blenis, John

BMC biology

2011 Volume 9, Page(s) 69

Abstract: The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)- ... ...

Abstract	The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.
MeSH term(s)	Animals ; Glycolysis ; Humans ; Mutation/genetics ; Neoplasms/metabolism ; Neoplasms/therapy ; Signal Transduction ; Tuberous Sclerosis/metabolism
Language	English
Publishing date	2011-10-21
Publishing country	England
Document type	Editorial ; Review
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/1741-7007-9-69
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Article ; Online: Appetite for destruction

Blenis John / Csibi Alfredo

BMC Biology, Vol 9, Iss 1, p

the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors

2011 Volume 69

Abstract: Abstract The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex ( ...

Abstract	Abstract The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro . In research published in Cell and Bioscience , Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model. See research article: http://www.cellandbioscience.com/content/1/1/34
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2011-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.

Bonazzi, Simone / d'Hennezel, Eva / Beckwith, Rohan E J / Xu, Lei / Fazal, Aleem / Magracheva, Anna / Ramesh, Radha / Cernijenko, Artiom / Antonakos, Brandon / Bhang, Hyo-Eun C / Caro, Roxana García / Cobb, Jennifer S / Ornelas, Elizabeth / Ma, Xiaolei / Wartchow, Charles A / Clifton, Matthew C / Forseth, Ry R / Fortnam, Bethany Hughes / Lu, Hongbo /

Csibi, Alfredo / Tullai, Jennifer / Carbonneau, Seth / Thomsen, Noel M / Larrow, Jay / Chie-Leon, Barbara / Hainzl, Dominik / Gu, Yi / Lu, Darlene / Meyer, Matthew J / Alexander, Dylan / Kinyamu-Akunda, Jacqueline / Sabatos-Peyton, Catherine A / Dales, Natalie A / Zécri, Frédéric J / Jain, Rishi K / Shulok, Janine / Wang, Y Karen / Briner, Karin / Porter, Jeffery A / Tallarico, John A / Engelman, Jeffrey A / Dranoff, Glenn / Bradner, James E / Visser, Michael / Solomon, Jonathan M

Cell chemical biology

2023 Volume 30, Issue 3, Page(s) 235–247.e12

Abstract: Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 ... ...

Abstract	Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.
MeSH term(s)	Animals ; Humans ; Mice ; Ikaros Transcription Factor ; Immunotherapy ; Neoplasms/therapy ; Neoplasms/metabolism ; T-Lymphocytes, Regulatory/metabolism ; Transcription Factors/metabolism
Chemical Substances	Ikaros Transcription Factor (148971-36-2) ; IKZF2 protein, human ; Transcription Factors ; Ikzf2 protein, mouse
Language	English
Publishing date	2023-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.02.005
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Article ; Online: The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis.

Sanchez, Anthony M J / Candau, Robin B / Csibi, Alfredo / Pagano, Allan F / Raibon, Audrey / Bernardi, Henri

American journal of physiology. Cell physiology

2012 Volume 303, Issue 5, Page(s) C475–85

Abstract: The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of ... ...

Abstract	The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.
MeSH term(s)	AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Energy Metabolism/physiology ; Gene Expression Regulation, Enzymologic/physiology ; Humans ; Muscle, Skeletal/enzymology ; Muscle, Skeletal/metabolism
Chemical Substances	AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2012-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00125.2012
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Article ; Online: Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.

Csibi, Alfredo / Communi, David / Müller, Nathalie / Bottari, Serge P

PloS one

2010 Volume 5, Issue 4, Page(s) e10070

Abstract: Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be ... ...

Abstract	Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2)(*-)-dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473) and Thr(308) as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr(156/139), close to their active site Asp(166/149), in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein nitration as a major mechanism in the regulation of Ang II and insulin signaling pathways and more particularly as a key regulator of protein kinase activity.
MeSH term(s)	Angiotensin II/pharmacology ; Animals ; Cells, Cultured ; Glucose Transporter Type 4/antagonists & inhibitors ; Glucose Transporter Type 4/metabolism ; Humans ; Insulin/pharmacology ; Insulin Receptor Substrate Proteins/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/cytology ; Nitrates/metabolism ; Protein Transport ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Tyrosine/metabolism
Chemical Substances	Glucose Transporter Type 4 ; Insulin ; Insulin Receptor Substrate Proteins ; Irs1 protein, rat ; Irs2 protein, rat ; Nitrates ; Angiotensin II (11128-99-7) ; Tyrosine (42HK56048U) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2010-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0010070
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Article ; Online: Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells.

Li, Jing / Csibi, Alfredo / Yang, Sun / Hoffman, Gregory R / Li, Chenggang / Zhang, Erik / Yu, Jane J / Blenis, John

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 1, Page(s) E21–9

Abstract: The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid ... ...

Abstract	The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid synthesis; and autophagy. Deregulation of the mTORC1 pathway is found in cancer as well as genetic disorders such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally suppress proliferation rather than induce apoptosis. Therefore, it is critical to use alternative strategies to induce death of cells with activated mTORC1. In this study, a small-molecule screen has revealed that the combination of glutaminase (GLS) and heat shock protein 90 (Hsp90) inhibitors selectively triggers death of TSC2-deficient cells. At a mechanistic level, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitizes these cells to endoplasmic reticulum (ER) stress. Thus, Hsp90 inhibition drives accumulation of unfolded protein and ER stress. When combining proteotoxic stress with oxidative stress by depletion of the intracellular antioxidant glutathione by GLS inhibition, acute cell death is observed in cells with activated mTORC1 signaling. This study suggests that this combination strategy may have the potential to be developed into a therapeutic use for the treatment of mTORC1-driven tumors.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Benzoquinones/pharmacology ; Cell Line, Tumor ; Cell Shape/drug effects ; Cell Survival/drug effects ; Glutamate Dehydrogenase/antagonists & inhibitors ; Glutamate Dehydrogenase/metabolism ; Glutaminase/antagonists & inhibitors ; Glutaminase/metabolism ; Glutamine/metabolism ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Lactams, Macrocyclic/pharmacology ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Models, Biological ; Multiprotein Complexes/metabolism ; Oxidation-Reduction/drug effects ; Phenotype ; Sirolimus/pharmacology ; Small Molecule Libraries/pharmacology ; Sulfides/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Thiadiazoles/pharmacology ; Tuberous Sclerosis/metabolism ; Tuberous Sclerosis/pathology ; Tumor Suppressor Proteins/deficiency ; Tumor Suppressor Proteins/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	Benzoquinones ; HSP90 Heat-Shock Proteins ; Lactams, Macrocyclic ; Multiprotein Complexes ; Small Molecule Libraries ; Sulfides ; Thiadiazoles ; Tumor Suppressor Proteins ; bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide ; Glutamine (0RH81L854J) ; tanespimycin (4GY0AVT3L4) ; tuberous sclerosis complex 2 protein (4JG2LF96VF) ; Glutamate Dehydrogenase (EC 1.4.1.2) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Glutaminase (EC 3.5.1.2) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2015-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1417015112
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Article ; Online: The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation.

Csibi, Alfredo / Lee, Gina / Yoon, Sang-Oh / Tong, Haoxuan / Ilter, Didem / Elia, Ilaria / Fendt, Sarah-Maria / Roberts, Thomas M / Blenis, John

Current biology : CB

2014 Volume 24, Issue 19, Page(s) 2274–2280

Abstract: Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation. Glutamine is ... ...

Abstract	Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5' untranslated region (5'UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN.
MeSH term(s)	Cell Line ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Eukaryotic Initiation Factors/genetics ; Eukaryotic Initiation Factors/metabolism ; Glutaminase/metabolism ; Glutamine/metabolism ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Mitochondria/metabolism ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Phosphorylation ; Real-Time Polymerase Chain Reaction ; Ribosomal Protein S6 Kinases, 70-kDa/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; Eukaryotic Initiation Factors ; MYCBP protein, human ; Multiprotein Complexes ; Transcription Factors ; eIF-4B ; Glutamine (0RH81L854J) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; ribosomal protein S6 kinase, 70kD, polypeptide 1 (EC 2.7.11.1) ; Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2014-09-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2014.08.007
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Zs.A 3208: Show issues

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Article ; Online: eIF3-f function in skeletal muscles: to stand at the crossroads of atrophy and hypertrophy.

Csibi, Alfredo / Tintignac, Lionel A / Leibovitch, Marie Pierre / Leibovitch, Serge A

Cell cycle (Georgetown, Tex.)

2008 Volume 7, Issue 12, Page(s) 1698–1701

Abstract: The control of muscle cell size is a physiological process balanced by a fine tuning between protein synthesis and protein degradation. MAFbx/Atrogin-1 is a muscle specific E3 ubiquitin ligase upregulated during disuse, immobilization and fasting or ... ...

Abstract	The control of muscle cell size is a physiological process balanced by a fine tuning between protein synthesis and protein degradation. MAFbx/Atrogin-1 is a muscle specific E3 ubiquitin ligase upregulated during disuse, immobilization and fasting or systemic diseases such as diabetes, cancer, AIDS and renal failure. This response is necessary to induce a rapid and functional atrophy. To date, the targets of MAFbx/Atrogin-1 in skeletal muscle remain to be identified. We have recently presented evidence that eIF3-f, a regulatory subunit of the eukaryotic translation factor eIF3 is a key target that accounts for MAFbx/Atrogin-1 function in muscle atrophy. More importantly, we showed that eIF3-f acts as a "translational enhancer" that increases the efficiency of the structural muscle proteins synthesis leading to both in vitro and in vivo muscle hypertrophy. We propose that eIF3-f subunit, a mTOR/S6K1 scaffolding protein in the IGF-1/Akt/mTOR dependent control of protein translation, is a positive actor essential to the translation of specific mRNAs probably implicated in muscle hypertrophy. The central role of eIF3-f in both the atrophic and hypertrophic pathways will be discussed in the light of its promising potential in muscle wasting therapy.
MeSH term(s)	Animals ; Eukaryotic Initiation Factor-3/antagonists & inhibitors ; Eukaryotic Initiation Factor-3/chemistry ; Eukaryotic Initiation Factor-3/physiology ; Humans ; Hypertrophy ; Muscle Proteins/chemistry ; Muscle Proteins/metabolism ; Muscle, Skeletal/growth & development ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/etiology ; Muscular Atrophy/genetics ; Muscular Atrophy/metabolism ; Protein Biosynthesis ; Protein Kinases/metabolism ; Protein Subunits/physiology ; Ribosomal Protein S6 Kinases/metabolism ; SKP Cullin F-Box Protein Ligases/chemistry ; SKP Cullin F-Box Protein Ligases/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases ; Wasting Syndrome/therapy
Chemical Substances	Eukaryotic Initiation Factor-3 ; Muscle Proteins ; Protein Subunits ; Fbxo32 protein, mouse (EC 2.3.2.27) ; SKP Cullin F-Box Protein Ligases (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1)
Keywords	covid19
Language	English
Publishing date	2008-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.7.12.6090
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Article ; Online: Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.

Alfredo Csibi / David Communi / Nathalie Müller / Serge P Bottari

PLoS ONE, Vol 5, Iss 4, p e

2010 Volume 10070

Abstract	Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2)(*-)-dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473) and Thr(308) as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr(156/139), close to their active site Asp(166/149), in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein nitration as a major mechanism in the regulation of Ang II and ...
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: eIF3f: a central regulator of the antagonism atrophy/hypertrophy in skeletal muscle.

Sanchez, Anthony M J / Csibi, Alfredo / Raibon, Audrey / Docquier, Aurélie / Lagirand-Cantaloube, Julie / Leibovitch, Marie-Pierre / Leibovitch, Serge A / Bernardi, Henri

The international journal of biochemistry & cell biology

2013 Volume 45, Issue 10, Page(s) 2158–2162

Abstract: The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that ... ...

Abstract	The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f plays a central role in skeletal muscle size maintenance. Accordingly, eIF3f overexpression results in hypertrophy through modulation of protein synthesis via the mTORC1 pathway. Importantly, eIF3f was described as a target of the E3 ubiquitin ligase MAFbx/atrogin-1 for proteasome-mediated breakdown under atrophic conditions. The biological importance of the MAFbx/atrogin-1-dependent targeting of eFI3f is highlighted by the finding that expression of an eIF3f mutant insensitive to MAFbx/atrogin-1 polyubiquitination is associated with enhanced protection against starvation-induced muscle atrophy. A better understanding of the precise role of this subunit should lead to the development of new therapeutic approaches to prevent or limit muscle wasting that prevails in numerous physiological and pathological states such as immobilization, aging, denervated conditions, neuromuscular diseases, AIDS, cancer, diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
MeSH term(s)	Animals ; Cell Proliferation ; Eukaryotic Initiation Factor-3/genetics ; Eukaryotic Initiation Factor-3/metabolism ; Humans ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/genetics ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology ; Protein Biosynthesis ; Signal Transduction
Chemical Substances	Eukaryotic Initiation Factor-3 ; Muscle Proteins
Keywords	covid19
Language	English
Publishing date	2013-06-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2013.06.001
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Inter-library loan at ZB MED

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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Order via subito

Inter-library loan at ZB MED

Full text online

More links

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito