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Science 296 (5569): 879-883

Copyright © 2002 by the American Association for the Advancement of Science

Regulation of SREBP Processing and Membrane Lipid Production by Phospholipids in Drosophila

I. Y. Dobrosotskaya,* A. C. Seegmiller,* M. S. Brown,dagger J. L. Goldstein,dagger R. B. Rawson

Animal cells exert exquisite control over the physical and chemical properties of their membranes, but the mechanisms are obscure. We show that phosphatidylethanolamine, the major phospholipid in Drosophila, controls the release of sterol regulatory element-binding protein (SREBP) from Drosophila cell membranes, exerting feedback control on the synthesis of fatty acids and phospholipids. The finding that SREBP processing is controlled by different lipids in mammals and flies (sterols and phosphatidylethanolamine, respectively) suggests that an essential function of SREBP is to monitor cell membrane composition and to adjust lipid synthesis accordingly.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: mike.brown{at} (M.S.B.); joe.goldstein{at} (J.L.G.)

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 287, 33897-33904
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 286, 26298-26307
   Abstract »    Full Text »    PDF »
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X. Wang, A. Diaz, L. Hao, B. Gancarz, J. A. den Boon, and P. Ahlquist (2011)
J. Virol. 85, 5494-5503
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A. Skoura and T. Hla (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J.-B. Demoulin, J. Ericsson, A. Kallin, C. Rorsman, L. Ronnstrand, and C.-H. Heldin (2004)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Mendel, K. Heinecke, H. Fyrst, and J. D. Saba (2003)
J. Biol. Chem. 278, 22341-22349
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Ranganathan (2003)
Science 299, 1677-1679
   Abstract »    Full Text »    PDF »
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Y. Shimada, T. Morita, and K. Sugiyama (2003)
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   Abstract »    Full Text »    PDF »
Suppression of the ELO-2 FA Elongation Activity Results in Alterations of the Fatty Acid Composition and Multiple Physiological Defects, Including Abnormal Ultradian Rhythms, in Caenorhabditis elegans.
M. Kniazeva, M. Sieber, S. McCauley, K. Zhang, J. L. Watts, and M. Han (2003)
Genetics 163, 159-169
   Abstract »    Full Text »    PDF »
Dietary Polyunsaturated Fats Regulate Rat Liver Sterol Regulatory Element Binding Proteins-1 and -2 in Three Distinct Stages and by Different Mechanisms.
J. Xu, H. Cho, S. O'Malley, J. H. Y. Park, and S. D. Clarke (2002)
J. Nutr. 132, 3333-3339
   Abstract »    Full Text »    PDF »
The Role of cAMP-dependent Signaling in Receptor-recognized Forms of alpha 2-Macroglobulin-induced Cellular Proliferation.
U. K. Misra, G. Akabani, and S. V. Pizzo (2002)
J. Biol. Chem. 277, 36509-36520
   Abstract »    Full Text »    PDF »
DegS and YaeL participate sequentially in the cleavage of RseA to activate the sigma E-dependent extracytoplasmic stress response.
B. M. Alba, J. A. Leeds, C. Onufryk, C. Z. Lu, and C. A. Gross (2002)
Genes & Dev. 16, 2156-2168
   Abstract »    Full Text »    PDF »
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A. Nohturfft and R. Losick (2002)
Science 296, 857-858
   Abstract »    Full Text »    PDF »

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