Involvement of Akt in ER-to-Golgi Transport of SCAP/SREBP: A Link between a Key Cell Proliferative Pathway and Membrane Synthesis
Autor: | Andrew J. Brown, Ika Kristiana, Jenny Wong, Ximing Du |
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Rok vydání: | 2006 |
Předmět: |
Cell Survival
Morpholines Golgi Apparatus CHO Cells Biology Endoplasmic Reticulum Transfection Phosphatidylinositol 3-Kinases symbols.namesake Cricetinae Animals Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Reverse Transcriptase Polymerase Chain Reaction Cell growth Endoplasmic reticulum Cell Membrane Intracellular Signaling Peptides and Proteins Membrane Proteins Articles Cell Biology Golgi apparatus Molecular biology Transport protein Sterol regulatory element-binding protein Cell biology Protein Transport Gene Expression Regulation Chromones symbols lipids (amino acids peptides and proteins) Cholesterol Esters Sterol regulatory element-binding protein 2 Proto-Oncogene Proteins c-akt Cell Division Sterol Regulatory Element Binding Protein 2 |
Zdroj: | Molecular Biology of the Cell. 17:2735-2745 |
ISSN: | 1939-4586 1059-1524 |
Popis: | Akt is a critical regulator of cell growth, proliferation, and survival that is activated by phosphatidylinositol 3-kinase (PI3K). We investigated the effect of PI3K inhibition on activation of sterol regulatory element binding protein-2 (SREBP-2), a master regulator of cholesterol homeostasis. SREBP-2 processing increased in response to various cholesterol depletion approaches (including statin treatment) and this increase was blunted by treatment with a potent and specific inhibitor of PI3K, LY294002, or when a plasmid encoding a dominant-negative form of Akt (DN-Akt) was expressed. LY294002 also suppressed SREBP-2 processing induced by insulin-like growth factor-1. Furthermore, LY294002 treatment down-regulated SREBP-2 or -1c gene targets and decreased cholesterol and fatty acid synthesis. Fluorescence microscopy studies indicated that LY294002 disrupts transport of the SREBP escort protein, SCAP, from the endoplasmic reticulum to the Golgi. This disruption was also shown by immunofluorescence staining when DN-Akt was expressed. Taken together, our studies indicate that the PI3K/Akt pathway is involved in SREBP-2 transport to the Golgi, contributing to the control of SREBP-2 activation. Our results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleologically because synthesis of new membrane is an absolute requirement for cell growth and proliferation. |
Databáze: | OpenAIRE |
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