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Targeting PI3K/mTOR signaling in cancer

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192441 Year: Pages: 93 DOI: 10.3389/978-2-88919-244-1 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Biology --- Medicine (General) --- Oncology
Added to DOAB on : 2015-11-16 15:44:59
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Abstract

The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments.

PI3K signalling

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194193 Year: Pages: 139 DOI: 10.3389/978-2-88919-419-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-10 11:59:06
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The PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.

mTOR in Human Diseases

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ISBN: 9783039210602 / 9783039210619 Year: Pages: 480 DOI: 10.3390/books978-3-03921-061-9 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General)
Added to DOAB on : 2019-06-26 08:44:06
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The mechanistic target of rapamycin (mTOR) is a major signaling intermediary that coordinates favorable environmental conditions with cell growth. Indeed, as part of two functionally distinct protein complexes, named mTORC1 and mTORC2, mTOR regulates a variety of cellular processes, including protein, lipid, and nucleotide synthesis, as well as autophagy. Over the last two decades, major molecular advances have been made in mTOR signaling and have revealed the complexity of the events implicated in mTOR function and regulation. In parallel, the role of mTOR in diverse pathological conditions has also been identified, including in cancer, hamartoma, neurological, and metabolic diseases. Through a series of articles, this book focuses on the role played by mTOR in cellular processes, metabolism in particular, and highlights a panel of human diseases for which mTOR inhibition provides or might provide benefits. It also addresses future studies needed to further characterize the role of mTOR in selected disorders, which will help design novel therapeutic approaches. It is therefore intended for everyone who has an interest in mTOR biology and its application in human pathologies.

Keywords

acute myeloid leukemia --- metabolism --- mTOR --- PI3K --- phosphorylation --- epithelial to mesenchymal transition --- mTOR inhibitor --- pulmonary fibrosis --- transcriptomics --- miRNome --- everolimus --- mTOR --- thyroid cancer --- sodium iodide symporter (NIS)/SLC5A5 --- dopamine receptor --- autophagy --- AKT --- mTOR --- AMPK --- mTOR --- Medulloblastoma --- MBSCs --- mTOR --- T-cell acute lymphoblastic leukemia --- targeted therapy --- combination therapy --- mTOR --- metabolic diseases --- glucose and lipid metabolism --- anesthesia --- neurotoxicity --- synapse --- mTOR --- neurodevelopment --- mTOR --- rapamycin --- autophagy --- protein aggregation --- methamphetamine --- schizophrenia --- tumour cachexia --- mTOR --- signalling --- metabolism --- proteolysis --- lipolysis --- mTOR --- mTORC1 --- mTORC2 --- rapamycin --- rapalogues --- rapalogs --- mTOR inhibitors --- senescence --- ageing --- aging --- cancer --- neurodegeneration --- immunosenescence --- senolytics --- biomarkers --- leukemia --- cell signaling --- metabolism --- apoptosis --- miRNA --- mTOR inhibitors --- mTOR --- tumor microenvironment --- angiogenesis --- immunotherapy --- fluid shear stress --- melatonin --- chloral hydrate --- nocodazole --- MC3T3-E1 cells --- primary cilia --- mTOR complex --- metabolic reprogramming --- cancer --- microenvironment --- nutrient sensor --- oral cavity squamous cell carcinoma (OSCC) --- NVP-BEZ235 --- mTOR --- p70S6K --- mTOR --- advanced biliary tract cancers --- mTOR --- NGS --- illumina --- IonTorrent --- eIFs --- mTOR --- autophagy --- Parkinson’s disease --- mTOR --- PI3K --- cancer --- inhibitor --- therapy --- mTOR --- laminopathies --- lamin A/C --- Emery-Dreifuss muscular dystrophy (EDMD) --- Hutchinson-Gilford progeria syndrome (HGPS) --- autophagy --- cellular signaling --- metabolism --- bone remodeling --- ageing --- mTOR --- fructose --- glucose --- liver --- lipid metabolism --- gluconeogenesis --- Alzheimer’s disease --- autophagy --- mTOR signal pathway --- physical activity --- microRNA --- mTOR --- spermatogenesis --- male fertility --- Sertoli cells --- n/a

AMP-Activated Protein Kinase Signalling

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ISBN: 9783038976622 Year: Pages: 452 DOI: 10.3390/books978-3-03897-663-9 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Science (General) --- Biology
Added to DOAB on : 2019-03-21 14:08:22
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Abstract

Starting from a kinase of interest, AMP-activated protein kinase (AMPK) has gone far beyond an average biomolecule. Being expressed in all mammalian cell types and probably having a counterpart in every eukaryotic cell, AMPK has attracted interest in virtually all areas of biological research. Structural and biophysical insights have greatly contributed to a molecular understanding of this kinase. From good old protein biochemistry to modern approaches, such as systems biology and advanced microscopy, all disciplines have provided important information. Thus, multiple links to cellular events and subcellular localizations have been established. Moreover, the crucial involvement of AMPK in human health and disease has been evidenced. AMPK accordingly has moved from an interesting enzyme to a pharmacological target. However, despite our extensive current knowledge about AMPK, the growing community is busier than ever. This book provides a snapshot of recent and current AMPK research with an emphasis on work providing molecular insight, including but not limited to novel physiological and pathological functions, or regulatory mechanisms. Up-to-date reviews and research articles are included.

Keywords

exercise --- glucose uptake --- AMP-activated protein kinase --- TBC1D4 --- AS160 --- AMP-activated protein kinase --- developmental origins of health and disease (DOHaD) --- hypertension --- kidney disease --- nutrient-sensing signals --- oxidative stress --- renin-angiotensin system --- AMPK --- autophagy --- co-expression --- microarrays --- 3T3-L1 --- adipocyte --- differentiation --- AMPK --- tight junctions --- epithelial cells --- ZO-1 --- par complex --- MDCK --- nectin-afadin --- adherent junctions --- TAK1 --- AMPK --- phosphorylation --- AMPK kinase --- endothelial nitric-oxide synthase --- vasodilation --- phenylephrine --- vasoconstriction --- endothelial cells --- ionomycin --- AMPK --- liver --- lipid metabolism --- fatty acid oxidation --- indirect calorimetry --- atrophy --- regrowth --- sirtuin 1 (SIRT1) --- peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) --- heat shock protein --- fiber-type --- AMPK --- monocytes --- macrophages --- differentiation --- autophagy --- AML --- MDS --- CML --- CMML --- pregnancy --- catechol-O-methyltransferase --- 2-methoxyestradiol --- preeclampsia --- gestational diabetes mellitus --- AMPK --- IL-1? --- NLRP3 --- nutrition --- dietary fatty acids --- metabolic-inflammation --- nutrigenomics --- AMPK --- LKB1 --- autophagy --- proteasome --- hypertrophy --- atrophy --- skeletal muscle --- AICAR --- mTOR --- protein synthesis --- AMPK --- epigenetics --- chromatin remodeling --- histone modification --- DNA methylation --- medulloblastoma --- sonic hedgehog --- AMPK --- AMP-activated protein kinase (AMPK) --- spermatozoa --- motility --- mitochondria --- membranes --- signaling --- stress --- assisted reproduction techniques --- AMP-activated protein kinase --- epigenetics --- protein acetylation --- KATs --- HDACs --- acetyl-CoA --- NAD+ --- AMP-activated protein kinase --- glycogen --- exercise --- metabolism --- cellular energy sensing --- energy utilization --- liver --- skeletal muscle --- metabolic disease --- glycogen storage disease --- resveratrol --- AMPK --- hepatocyte --- liver --- steatosis --- transporter --- carrier --- pump --- membrane --- energy deficiency --- AMPK --- infection --- mycobacteria --- host defense --- energy metabolism --- AMPK --- activation loop --- AID --- ?-linker --- ?-linker --- CBS --- LKB1 --- CaMKK2 --- ?RIM --- hypothalamus --- adenosine monophosphate-activated protein kinase --- adipose tissue --- food intake --- adaptive thermogenesis --- beiging --- AMPK --- HDAC4/5 --- p70S6K --- MyHC I(?), motor endplate remodeling --- soleus muscle --- mechanical unloading --- hindlimb suspension --- AMPK --- synaptic activation --- PKA --- CREB --- soluble Adenylyl cyclase --- Immediate early genes --- transcription --- AMPK --- autophagy --- metabolism --- mTOR --- ULK --- AMP-activated protein kinase --- protein kinase B --- Akt --- insulin signalling --- A769662 --- endothelial function --- n/a

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