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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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          Growing roles for the mTOR pathway.

          Dos Sarbassov, Siraj M. Ali, David Sabatini (2005)
          The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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            Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.

            Jay Horton, Nila A Shah, Janet A Warrington … (2003)
            The synthesis of fatty acids and cholesterol, the building blocks of membranes, is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs as a result of gene knockout of SREBP cleavage-activating protein (SCAP), a protein required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. A total of 1,003 genes showed statistically significant increased expression in livers of transgenic SREBP-1a mice, 505 increased in livers of transgenic SREBP-2 mice, and 343 showed decreased expression in Scap-/- livers. A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice. Of these 33 genes, 13 were previously identified as direct targets of SREBP action. Of the remaining 20 genes, 13 encode enzymes or carrier proteins involved in cholesterol metabolism, 3 participate in fatty acid metabolism, and 4 have no known connection to lipid metabolism. Through application of stringent combinatorial criteria, the transgenic/knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.
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              Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.

              J Repa, G Liang, J. Ou … (2000)
              The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Metab
                Title: Cell Metabolism
                Publisher: Cell Press
                ISSN (Print): 1550-4131
                ISSN (Electronic): 1932-7420
                Publication date PMC-release: 03 September 2008
                Publication date (Print): 03 September 2008
                Volume: 8
                Issue: 3-3
                Pages: 224-236
                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

                Article
                Publisher ID: CMET480
                DOI: 10.1016/j.cmet.2008.07.007
                PMC ID: 2593919
                PubMed ID: 18762023
                SO-VID: 279e28d7-68b4-42d1-905a-06369cf6b3ae
                Copyright © © 2008 ELL & Excerpta Medica.
                License:

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

                History
                Date received : 22 December 2007
                Date revision received : 12 May 2008
                Date accepted : 25 July 2008
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: humdisease,signaling
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: humdisease, signaling

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