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Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression Harding HP; Zhang Y; Khersonsky S; Marciniak S; Scheuner D; Kaufman RJ; Javitt N; Chang YT; Ron DCell Metab 2005[Dec]; 2 (6): 361-71Phosphorylation of translation initiation factor 2alpha (eIF2alpha) coordinates a translational and transcriptional program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. A screen for small molecule activators of the ISR identified two related compounds that also activated sterol-regulated genes by blocking cholesterol biosynthesis at the level of CYP51. Ketoconazole, a known CYP51 inhibitor, had similar effects, establishing that perturbed flux of precursors to cholesterol activates the ISR. Surprisingly, compound-mediated activation of sterol-regulated genes was enhanced in cells with an ISR-blocking mutation in the regulatory phosphorylation site of eIF2alpha. Furthermore, induction of the ISR by an artificial drug-activated eIF2alpha kinase reduced the level of active sterol regulatory element binding protein (SREBP) and sterol-regulated mRNAs. These findings suggest a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress.|*Gene Expression Regulation[MESH]|Animals[MESH]|Blotting, Northern[MESH]|Cell Line[MESH]|Cell Survival[MESH]|Cholesterol/metabolism[MESH]|Chromatography, Thin Layer[MESH]|Dose-Response Relationship, Drug[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Eukaryotic Initiation Factor-2/*metabolism[MESH]|Immunoblotting[MESH]|Ketoconazole/pharmacology[MESH]|Lipids/chemistry[MESH]|Mice[MESH]|Models, Biological[MESH]|Models, Chemical[MESH]|Phosphorylation[MESH]|Protein Biosynthesis[MESH]|RNA, Messenger/metabolism[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|Sterol Regulatory Element Binding Proteins/metabolism[MESH]|Sterols/*metabolism[MESH]|Time Factors[MESH]|Transcription, Genetic[MESH] |
