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      SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth

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          Summary

          Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.

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          Most cited references 58

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          AKT/PKB signaling: navigating downstream.

          The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.
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            TOR signaling in growth and metabolism.

            The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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              TSC2 mediates cellular energy response to control cell growth and survival.

              Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for Tuberous Sclerosis Complex. The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation. Here, we describe that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway. Under energy starvation conditions, the AMP-activated protein kinase (AMPK) phosphorylates TSC2 and enhances its activity. Phosphorylation of TSC2 by AMPK is required for translation regulation and cell size control in response to energy deprivation. Furthermore, TSC2 and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis. These observations demonstrate a model where TSC2 functions as a key player in regulation of the common mTOR pathway of protein synthesis, cell growth, and viability in response to cellular energy levels.
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                Author and article information

                Affiliations
                [1 ]Gene Expression Analysis Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                [2 ]Signal Transduction Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                [3 ]Developmental Signalling Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                [4 ]Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                [5 ]Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE UK
                [6 ]Cancer Research UK Biomedical Magnetic Resonance Research Group, The Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK
                Author notes
                []Corresponding author almut.schulze@ 123456cancer.org.uk
                [7]

                These authors contributed equally to this work

                Contributors
                Journal
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                03 September 2008
                03 September 2008
                : 8
                : 3-3
                : 224-236
                2593919
                18762023
                CMET480
                10.1016/j.cmet.2008.07.007
                © 2008 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                Categories
                Article

                Cell biology

                signaling, humdisease

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