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      PF-4708671 Activates AMPK Independently of p70S6K1 Inhibition

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          Abstract

          The P70 ribosomal protein S6 kinase 1 (P70S6K1) is activated by the mammalian target of rapamycin (mTORC1) and regulates proliferation, growth, and metabolism. PF-4708671 is a novel, cell-permeable, has been proposed to be a highly specific inhibitor of p70S6K1. It is used in micromolar concentration range to dissect signaling pathways downstream of mTORC1 and to study the function of p70S6K1. Here we show that PF-4708671 induces AMP-activated protein kinase (AMPK) phosphorylation and activation in immortalized mouse embryonic fibroblasts (MEF) independently of p70S6K1, due to specific inhibition of mitochondrial respiratory chain Complex I.

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          Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1.

          Issam Ben-Sahra, Jessica J Howell, John Asara … (2013)
          Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.
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            Dissecting the role of mTOR: lessons from mTOR inhibitors.

            Ryan Dowling, Ivan Topisirovic, Bruno Fonseca … (2010)
            Recent years have observed significant advances in our understanding of how the serine/threonine kinase target of rapamycin (TOR) controls key cellular processes such as cell survival, growth and proliferation. Consistent with its role in cell proliferation, the mTOR pathway is frequently hyperactivated in a number of human malignancies and is thus considered to be an attractive target for anti-cancer therapy. Rapamycin and its analogs (rapalogs) function as allosteric inhibitors of mTORC1 and are currently used in the treatment of advanced renal cell carcinoma. Rapamycin and its derivatives bind to the small immunophilin FKBP12 to inhibit mTORC1 signalling through a poorly understood mechanism. Rapamycin/FKBP12 efficiently inhibit some, but not all, functions of mTOR and hence much interest has been placed in the development of drugs that target the kinase activity of mTOR directly. Several novel active-site inhibitors of mTOR, which inhibit both mTORC1 and mTORC2, were developed in the last year. In this manuscript, we provide a brief outline of our current understanding of the mTOR signalling pathway and review the molecular underpinnings of the action of rapamycin and novel active-site mTOR inhibitors as well as potential advantages and caveats associated with the use of these drugs in the treatment of cancer. Copyright 2009 Elsevier B.V. All rights reserved.
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              Cross-talk between AMPK and mTOR in regulating energy balance.

              Xiang Yan, Jian Ji, Jia Xu (2011)
              Energy balance is maintained by a complex homeostatic system involving some signaling pathways and "nutrient sensors" in multiple tissues and organs. Any defect associated with the pathways can lead to metabolic disorders including obesity, type 2 diabetes, and the metabolic syndrome. The 5'-adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) appear to play a significant role in the intermediary metabolism of these diseases. AMPK is involved in the fundamental regulation of energy balance at the whole body level by responding to hormonal and nutrient signals in the central nervous system and peripheral tissues that modulate food intake and energy expenditure. Mammalian target of rapamycin (mTOR),is one of the downstream targets of AMPK functions as an intracellular nutrient sensor to control protein synthesis, cell growth, and metabolism. Recent research demonstrated the possible interplay between mTOR and AMPK signaling pathways. In this review, we will present current knowledge of AMPK and mTOR pathways in regulating energy balance and demonstrate the convergence between these two pathways.
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                Author and article information

                Contributors
                Petras Dzeja: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 9 September 2014
                Volume: 9
                Issue: 9
                Electronic Location Identifier: e107364
                Affiliations
                [1 ]Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
                [2 ]Monique and Jacques Roboh Department of Genetic Research, and Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [3 ]Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [4 ]Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel
                Mayo Clinic, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GWV JBT RH. Performed the experiments: GWV AS JKA AA RH. Analyzed the data: GWV AS JKA AA. Contributed reagents/materials/analysis tools: GWV AS RH. Wrote the paper: GWV JBT RH.

                Article
                Publisher ID: PONE-D-13-38990
                DOI: 10.1371/journal.pone.0107364
                PMC ID: 4159345
                SO-VID: e4213bff-f8cd-4df4-9047-6c8c20fe532a
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 23 September 2013
                Date accepted : 15 August 2014
                Page count
                Pages: 5
                Funding
                This work was financed in part by the Tel-Aviv Sourasky Medical Center and Mr. Daniel Levin donation (GWV); the Israeli Ministry of Health grant #5938 (GWV); The Israeli Cancer Association (GWV); and Israeli Science Foundation (ISF) grant #1462 (AS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Bioenergetics
                Subject: Energy-Producing Organelles
                Subject: Enzymology
                Subject: Enzymes
                Subject: Metabolism
                Subject: Oxygen Metabolism
                Subject: Cytochemistry
                Subject: Biotechnology
                Subject: Small Molecules
                Subject: Cell Biology
                Subject: Signal Transduction
                Subject: Cell Signaling
                Subject: Cellular Structures and Organelles
                Subject: Molecular Cell Biology
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse Models

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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