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mTORc1 AND Beta cells

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https://www.readbyqxmd.com/read/27854154/small-gtpases-in-c-elegans-metabolism
#1
Daniel Z Bar, Chayki Charar, Yosef Gruenbaum
The mechanistic target of rapamycin (mTOR) is an evolutionary conserved protein with a serine/threonine kinase activity that regulates cell growth, proliferation, motility, survival, protein synthesis, autophagy and transcription. It is embedded in 2 large protein complexes: mTORC1 and mTORC2. Regulation of specific mTOR pathway functions depends on multiple GTPases, that act either as regulators of mTOR protein complexes, coupling energy availability with mTORC1 activity, or as downstream effectors of both mTORC1 and mTORC2...
November 17, 2016: Small GTPases
https://www.readbyqxmd.com/read/27609771/insulin-promotes-proliferation-and-fibrosing-responses-in-activated-pancreatic-stellate-cells
#2
Jiayue Yang, Richard T Waldron, Hsin-Yuan Su, Aune Moro, Hui-Hua Chang, Guido Eibl, Kevin Ferreri, Fouad R Kandeel, Aurelia Lugea, Ling Li, Stephen J Pandol
Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27552145/combining-high-content-imaging-and-phenotypic-classification-analysis-of-senescence-associated-beta-galactosidase-staining-to-identify-regulators-of-oncogene-induced-senescence
#3
Keefe T Chan, Lassi Paavolainen, Katherine M Hannan, Amee J George, Ross D Hannan, Kaylene J Simpson, Peter Horvath, Richard B Pearson
Hyperactivation of the PI3K/AKT/mTORC1 signaling pathway is a hallmark of the majority of sporadic human cancers. Paradoxically, chronic activation of this pathway in nontransformed cells promotes senescence, which acts as a significant barrier to malignant progression. Understanding how this oncogene-induced senescence is maintained in nontransformed cells and conversely how it is subverted in cancer cells will provide insight into cancer development and potentially identify novel therapeutic targets. High-throughput screening provides a powerful platform for target discovery...
September 2016: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/27540684/pebp1-a-raf-kinase-inhibitory-protein-negatively-regulates-starvation-induced-autophagy-by-direct-interaction-with-lc3
#4
Hae Sook Noh, Young-Sool Hah, Sahib Zada, Ji Hye Ha, Gyujin Sim, Jin Seok Hwang, Trang Huyen Lai, Huynh Quoc Nguyen, Jae-Yong Park, Hyun Joon Kim, June-Ho Byun, Jong Ryeal Hahm, Kee Ryeon Kang, Deok Ryong Kim
Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubule- associated protein 1 light chain 3 β) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL)...
November 2016: Autophagy
https://www.readbyqxmd.com/read/27512079/quantitative-non-canonical-amino-acid-tagging-quancat-proteomics-identifies-distinct-patterns-of-protein-synthesis-rapidly-induced-by-hypertrophic-agents-in-cardiomyocytes-revealing-new-aspects-of-metabolic-remodeling
#5
Rui Liu, Justin W Kenney, Antigoni Manousopoulou, Harvey E Johnston, Makoto Kamei, Christopher H Woelk, Jianling Xie, Michael Schwarzer, Spiros D Garbis, Christopher G Proud
Cardiomyocytes undergo growth and remodeling in response to specific pathological or physiological conditions. In the former, myocardial growth is a risk factor for cardiac failure and faster protein synthesis is a major factor driving cardiomyocyte growth. Our goal was to quantify the rapid effects of different pro-hypertrophic stimuli on the synthesis of specific proteins in ARVC and to determine whether such effects are caused by alterations on mRNA abundance or the translation of specific mRNAs. Cardiomyocytes have very low rates of protein synthesis, posing a challenging problem in terms of studying changes in the synthesis of specific proteins, which also applies to other nondividing primary cells...
October 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27240166/tumor-suppression-in-basal-keratinocytes-via-dual-non-cell-autonomous-functions-of-a-na-k-atpase-beta-subunit
#6
Julia Hatzold, Filippo Beleggia, Hannah Herzig, Janine Altmüller, Peter Nürnberg, Wilhelm Bloch, Bernd Wollnik, Matthias Hammerschmidt
The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress)...
2016: ELife
https://www.readbyqxmd.com/read/27239959/pten-negatively-regulates-mtorc2-formation-and-signaling-in-grade-iv-glioma-via-rictor-hyperphosphorylation-at-thr1135-and-direct-the-mode-of-action-of-an-mtorc1-2-inhibitor
#7
K Bhattacharya, S Maiti, C Mandal
To investigate the role of PTEN (phosphatase and tensin homolog) in mammalian target of rapamycin complex 2 (mTORC2) signaling in glioblastoma multiforme (GBM), we found higher activation of mTORC2 in PTEN(mu) cells, as evidenced by enhanced phosphorylation of mTOR (Ser2481), AKT (Ser473) and glycogen synthase kinase 3 beta (GSK3β) (Ser9) as compared with PTEN(wt) cells. In addition, PTEN(wt) cells upon PTEN depletion showed mTORC2 activation. The reduced mTORC2 signaling in PTEN(wt) cells was related to higher Rictor phosphorylation at Thr1135 residue...
2016: Oncogenesis
https://www.readbyqxmd.com/read/26884434/salmonella-suppresses-the-trif-dependent-type-i-interferon-response-in-macrophages
#8
Katherine A Owen, C J Anderson, James E Casanova
UNLABELLED: Salmonella enterica is an intracellular pathogen that causes diseases ranging from gastroenteritis to typhoid fever. Salmonella bacteria trigger an autophagic response in host cells upon infection but have evolved mechanisms for suppressing this response, thereby enhancing intracellular survival. We recently reported that S. enterica serovar Typhimurium actively recruits the host tyrosine kinase focal adhesion kinase (FAK) to the surface of the Salmonella-containing vacuole (SCV) (K...
2016: MBio
https://www.readbyqxmd.com/read/26818915/mtorc1-pathway-mediates-beta-cell-compensatory-proliferation-in-60%C3%A2-partial-pancreatectomy-mice
#9
Wenyi Li, Hongli Zhang, Aifang Nie, Qicheng Ni, Fengying Li, Guang Ning, Xiaoying Li, Yanyun Gu, Qidi Wang
Beta cell replication is the major component for maintenance of beta cell mass in adult rodents; however, little is known about what is the earliest signals that initiate rodent beta cell proliferation. The mTORC1 pathway integrates signals from growth factors and nutrients and regulates cell growth and survival. Here, we used normoglycemic 60 % partial-pancreatectomy (60 % Px) mouse model to determine whether mTORC1 pathway was required for compensatory beta cell proliferation. C57BL/6 J male mice were subjected to 60 % Px or sham operation, and subsequently treated with either rapamycin or vehicle for 7 days...
July 2016: Endocrine
https://www.readbyqxmd.com/read/26560525/amino-acid-sensing-and-activation-of-mechanistic-target-of-rapamycin-complex-1-implications-for-skeletal-muscle
#10
REVIEW
Daniel J Ham, Gordon S Lynch, René Koopman
PURPOSE OF REVIEW: This article evaluates recent studies on the mechanisms involved in sensing changes in amino acid availability and activation of the mechanistic target of rapamycin complex 1 (mTORC1). RECENT FINDINGS: mTORC1 is sensitive to changes in amino acid availability and a well known regulator of protein turnover. The mechanisms of amino acid sensing and mTORC1 signaling are emerging with multiple potential sensors (e.g., solute carrier family 38, member 9, lysosomal protein transmembrane 4 beta/solute carrier family 7, member 5-solute carrier family 3, member 2) and signal transducers (e...
January 2016: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/26463117/alternative-rapamycin-treatment-regimens-mitigate-the-impact-of-rapamycin-on-glucose-homeostasis-and-the-immune-system
#11
Sebastian I Arriola Apelo, Joshua C Neuman, Emma L Baar, Faizan A Syed, Nicole E Cummings, Harpreet K Brar, Cassidy P Pumper, Michelle E Kimple, Dudley W Lamming
Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin...
February 2016: Aging Cell
https://www.readbyqxmd.com/read/26462016/expression-and-activity-of-eif6-trigger-malignant-pleural-mesothelioma-growth-in-vivo
#12
Annarita Miluzio, Stefania Oliveto, Elisa Pesce, Luciano Mutti, Bruno Murer, Stefano Grosso, Sara Ricciardi, Daniela Brina, Stefano Biffo
eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials...
November 10, 2015: Oncotarget
https://www.readbyqxmd.com/read/26025205/the-critical-role-of-akt-in-cardiovascular-function
#13
REVIEW
Prasanna Abeyrathna, Yunchao Su
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1...
November 2015: Vascular Pharmacology
https://www.readbyqxmd.com/read/25812014/involvement-of-dna-pkcs-in-the-type-i-ifn-response-to-cpg-odns-in-conventional-dendritic-cells-in-tlr9-dependent-or-independent-manners
#14
Chi Ma, Narrissa P Spies, Ting Gong, Can Xin Jones, Wen-Ming Chu
CpG-ODNs activate dendritic cells (DCs) to produce interferon alpha (IFNα) and beta (IFNβ). Previous studies demonstrated that Toll-like receptor 9 (TLR9) deficient DCs exhibited a residual IFNα response to CpG-A, indicating that yet-unidentified molecules are also involved in induction of IFNα by CpG-A. Here, we report that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) but not Ku70 deficient BMDCs showed defective IFNα and IFNβ responses to CpG-A or CpG-B. Loss of both DNA-PKcs and TLR9 further reduced the IFNα response to CpG-A...
2015: PloS One
https://www.readbyqxmd.com/read/25797178/insulin-receptor-isoform-a-confers-a-higher-proliferative-capability-to-pancreatic-beta-cells-enabling-glucose-availability-and-igf-i-signaling
#15
Oscar Escribano, Almudena Gómez-Hernández, Sabela Díaz-Castroverde, Carmen Nevado, Gema García, Yolanda F Otero, Liliana Perdomo, Nuria Beneit, Manuel Benito
The main compensatory response to insulin resistance is the pancreatic beta cell hyperplasia to account for increased insulin secretion. In fact, in a previous work we proposed a liver-pancreas endocrine axis with IGF-I (insulin-like growth factor type I) secreted by the liver acting on IRA insulin receptor in beta cells from iLIRKO mice (inducible Liver Insulin Receptor KnockOut) that showed a high IRA/IRB ratio. However, the role of insulin receptor isoforms in the IGF-I-induced beta cell proliferation as well as the underlying molecular mechanisms remain poorly understood...
July 5, 2015: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/25794661/rapamycin-can-restore-the-negative-regulatory-function-of-transforming-growth-factor-beta-1-in-high-grade-lymphomas
#16
Anna Sebestyén, Ágnes Márk, Melinda Hajdu, Noémi Nagy, Anna Molnár, Gyula Végső, Gábor Barna, László Kopper
TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells...
June 2015: Cytokine
https://www.readbyqxmd.com/read/25753754/fluocinolone-acetonide-is-a-potent-synergistic-factor-of-tgf-%C3%AE-3-associated-chondrogenesis-of-bone-marrow-derived-mesenchymal-stem-cells-for-articular-surface-regeneration
#17
Emilio Satoshi Hara, Mitsuaki Ono, Hai Thanh Pham, Wataru Sonoyama, Satoshi Kubota, Masaharu Takigawa, Takuya Matsumoto, Marian F Young, Bjorn R Olsen, Takuo Kuboki
Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3...
September 2015: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/25727005/tsc1-activates-tgf-%C3%AE-smad2-3-signaling-in-growth-arrest-and-epithelial-to-mesenchymal-transition
#18
Antje Thien, Mirja Tamara Prentzell, Birgit Holzwarth, Kathrin Kläsener, Ineke Kuper, Christopher Boehlke, Annika G Sonntag, Stefanie Ruf, Lars Maerz, Roland Nitschke, Sushma-Nagaraja Grellscheid, Michael Reth, Gerd Walz, Ralf Baumeister, Elke Neumann-Haefelin, Kathrin Thedieck
The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling. They suppress cell growth and proliferation by acting in a heteromeric complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1). In this study, we identify TSC1 as a component of the transforming growth factor β (TGF-β)-Smad2/3 pathway. Here, TSC1 functions independently of TSC2. TSC1 interacts with the TGF-β receptor complex and Smad2/3 and is required for their association with one another. TSC1 regulates TGF-β-induced Smad2/3 phosphorylation and target gene expression and controls TGF-β-induced growth arrest and epithelial-to-mesenchymal transition (EMT)...
March 9, 2015: Developmental Cell
https://www.readbyqxmd.com/read/25659819/rapamycin-induced-g1-cell-cycle-arrest-employs-both-tgf-%C3%AE-and-rb-pathways
#19
Amrita Chatterjee, Suman Mukhopadhyay, Kaity Tung, Deven Patel, David A Foster
The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of G1 cell cycle progression. Two key substrates of mTORC1 are ribosomal subunit S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4E-BP1). We reported previously that simultaneous knockdown of S6K and eIF4E causes a transforming growth factor-β (TGF-β)-dependent G1 cell cycle arrest in MDA-MB-231 human breast cancer cells. Rapamycin inhibits the phosphorylation of S6K at nano-molar concentrations in MDA-MB-231 cells; however, micro-molar concentrations of rapamycin are required to inhibit phosphorylation of 4E-BP1 - the phosphorylation of which liberates eIF4E to initiate translation...
May 1, 2015: Cancer Letters
https://www.readbyqxmd.com/read/25612620/atf4-gene-network-mediates-cellular-response-to-the-anticancer-pad-inhibitor-yw3-56-in-triple-negative-breast-cancer-cells
#20
Shu Wang, Xiangyun Amy Chen, Jing Hu, Jian-Kang Jiang, Yunfei Li, Ka Yim Chan-Salis, Ying Gu, Gong Chen, Craig Thomas, B Franklin Pugh, Yanming Wang
We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit cancer growth. However, the p53-independent anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, high-resolution genomic binding sites of ATF4 and CEBPB responsive to YW3-56 treatment were generated...
April 2015: Molecular Cancer Therapeutics
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