scholarly journals Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

2009 ◽  
Vol 187 (6) ◽  
pp. 859-874 ◽  
Author(s):  
Valérie Risson ◽  
Laetitia Mazelin ◽  
Mila Roceri ◽  
Hervé Sanchez ◽  
Vincent Moncollin ◽  
...  
Keyword(s):  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Premature Death ◽  
Whole Body ◽  
Independent Manner ◽  
Glycogen Accumulation ◽  
Mitochondrial Regulation ◽  
A Cell ◽  
Mtor Complex 1 ◽  
Basal Glucose Uptake

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.

Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 206-210
Author(s):  
Feng Chen ◽  
Bei Zhang
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Protein Kinase ◽  
Cell Viability ◽  
Cancer Cells ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Ovarian Cancer Cells ◽  
Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organization

2000 ◽  
Vol 113 (2) ◽  
pp. 315-324 ◽  
Author(s):  
P.C. Baciu ◽  
S. Saoncella ◽  
S.H. Lee ◽  
F. Denhez ◽  
D. Leuthardt ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Focal Adhesions ◽  
Cell Spreading ◽  
Cytoplasmic Domain ◽  
Cellular Protein ◽  
Actin Stress Fiber ◽  
Independent Manner ◽  
Intracellular Proteins ◽  
Central Regions ◽  
A Cell

Syndecan-4 is a cell surface heparan sulfate proteoglycan which, in cooperation with integrins, transduces signals for the assembly of focal adhesions and actin stress fibers in cells plated on fibronectin. The regulation of these cellular events is proposed to occur, in part, through the interaction of the cytoplasmic domains of these transmembrane receptors with intracellular proteins. To identify potential intracellular proteins that interact with the cytoplasmic domain of syndecan-4, we carried out a yeast two-hybrid screen in which the cytoplasmic domain of syndecan-4 was used as bait. As a result of this screen, we have identified a novel cellular protein that interacts with the cytoplasmic domain of syndecan-4 but not with those of the other three syndecan family members. The interaction involves both the membrane proximal and variable central regions of the cytoplasmic domain. We have named this cDNA and encoded protein syndesmos. Syndesmos is ubiquitously expressed and can be myristylated. Consistent with its myristylation and syndecan-4 association, syndesmos colocalizes with syndecan-4 in the ventral plasma membranes of cells plated on fibronectin. When overexpressed in NIH 3T3 cells, syndesmos enhances cell spreading, actin stress fiber and focal contact formation in a serum-independent manner.

Mechanism of estrogen receptor-dependent transcription in a cell-free system

1990 ◽  
Vol 10 (12) ◽  
pp. 6607-6612
Author(s):  
J F Elliston ◽  
S E Fawell ◽  
L Klein-Hitpass ◽  
S Y Tsai ◽  
M J Tsai ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Rna Polymerase Ii ◽  
Expression System ◽  
Steroid Receptor ◽  
Free Expression ◽  
Independent Manner ◽  
Free System ◽  
A Cell ◽  
Regulated Gene Expression ◽  
Cell Free Expression System

RNA synthesis was stimulated directly in a cell-free expression system by crude preparations of recombinant mouse estrogen receptor (ER). Receptor-stimulated transcription required the presence of estrogen response elements (EREs) in the test template and could be specifically inhibited by addition of competitor oligonucleotides containing EREs. Moreover, polyclonal antibodies directed against the DNA-binding region of ER inhibited ER-dependent transcription. In our cell-free expression system, hormone-free ER induced transcription in a hormone-independent manner. Evidence is presented suggesting that ER acts by facilitating the formation of a stable preinitiation complex at the target gene promoter and thus augments the initiation of transcription by RNA polymerase II. These observations lend support to our current understanding of the mechanism of steroid receptor-regulated gene expression and suggest strong conservation of function among members of the steroid receptor superfamily.

scholarly journals Noninvasive Whole-Body Imaging of Phosphatidylethanolamine as a Cell Death Marker Using99mTc-Duramycin During TNF-Induced SIRS

2018 ◽  
Vol 59 (7) ◽  
pp. 1140-1145 ◽  
Author(s):  
Tinneke Delvaeye ◽  
Leonie wyffels ◽  
Steven Deleye ◽  
Kelly Lemeire ◽  
Amanda Gonçalves ◽  
...  
Keyword(s):  
Cell Death ◽  
Whole Body ◽  
Whole Body Imaging ◽  
Body Imaging ◽  
A Cell

scholarly journals Distinct signaling and transcriptional pathways regulate peri-weaning development and cold-induced recruitment of beige adipocytes

2020 ◽  
Vol 117 (12) ◽  
pp. 6883-6889 ◽  
Author(s):  
Yixuan Wu ◽  
Melissa A. Kinnebrew ◽  
Vassily I. Kutyavin ◽  
Ajay Chawla
Keyword(s):  
Adipose Tissue ◽  
Maintenance Phase ◽  
Cell Types ◽  
Acid Oxidation ◽  
Mitochondrial Uncoupling ◽  
Independent Manner ◽  
Distinct Cell ◽  
Beige Adipocytes ◽  
B Cell Leukemia ◽  
A Cell

Adipose tissue provides a defense against starvation and environmental cold. These dichotomous functions are performed by three distinct cell types: energy-storing white adipocytes, and thermogenic beige and brown adipocytes. Previous studies have demonstrated that exposure to environmental cold stimulates the recruitment of beige adipocytes in the white adipose tissue (WAT) of mice and humans, a process that has been extensively investigated. However, beige adipose tissue also develops during the peri-weaning period in mice, a developmental program that remains poorly understood. Here, we address this gap in our knowledge using genetic, imaging, physiologic, and genomic approaches. We find that, unlike cold-induced recruitment in adult animals, peri-weaning development of beige adipocytes occurs in a temperature- and sympathetic nerve-independent manner. Instead, the transcription factor B cell leukemia/lymphoma 6 (BCL6) acts in a cell-autonomous manner to regulate the commitment but not the maintenance phase of beige adipogenesis. Genome-wide RNA-sequencing (seq) studies reveal that BCL6 regulates a core set of genes involved in fatty acid oxidation and mitochondrial uncoupling, which are necessary for development of functional beige adipocytes. Together, our findings demonstrate that distinct transcriptional and signaling mechanisms control peri-weaning development and cold-induced recruitment of beige adipocytes in mammals.

scholarly journals Akt/Protein Kinase B Promotes Organ Growth in Transgenic Mice

2002 ◽  
Vol 22 (8) ◽  
pp. 2799-2809 ◽  
Author(s):  
Tetsuo Shioi ◽  
Julie R. McMullen ◽  
Peter M. Kang ◽  
Pamela S. Douglas ◽  
Toshiyuki Obata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transgenic Mice ◽  
Cell Size ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Pi3k Pathway ◽  
Mutant Protein ◽  
Heart Weight ◽  
Heart Size ◽  
Constitutively Active

ABSTRACT One of the least-understood areas in biology is the determination of the size of animals and their organs. In Drosophila, components of the insulin receptor phosphoinositide 3-kinase (PI3K) pathway determine body, organ, and cell size. Several biochemical studies have suggested that Akt/protein kinase B is one of the important downstream targets of PI3K. To examine the role of Akt in the regulation of organ size in mammals, we have generated and characterized transgenic mice expressing constitutively active Akt (caAkt) or kinase-deficient Akt (kdAkt) specifically in the heart. The heart weight of caAkt transgenic mice was increased 2.0-fold compared with that of nontransgenic mice. The increase in heart size was associated with a comparable increase in myocyte cell size in caAkt mice. The kdAkt mutant protein attenuated the constitutively active PI3K-induced overgrowth of the heart, and the caAkt mutant protein circumvented cardiac growth retardation induced by a kinase-deficient PI3K mutant protein. Rapamycin attenuated caAkt-induced overgrowth of the heart, suggesting that the mammalian target of rapamycin (mTOR) or effectors of mTOR mediated caAkt-induced heart growth. In conclusion, Akt is sufficient to induce a marked increase in heart size and is likely to be one of the effectors of the PI3K pathway in mediating heart growth.

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