Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression
SCIE
SCOPUS
- Title
- Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression
- Authors
- Harding, HP; Zhang, YH; Khersonsky, S; Marciniak, S; Scheuner, D; Kaufman, RJ; Javitt, N; Chang, Young-Tae; Ron, D
- Date Issued
- 2005-12
- Publisher
- CELL PRESS
- Abstract
- Phosphorylation of translation initiation factor 2 alpha (eIF2 alpha) 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 eIF2a. Furthermore, induction of the ISR by an artificial drug-activated eIF2 alpha 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.
- Keywords
- UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; ELEMENT-BINDING PROTEINS; N-ACETYLGLUCOSAMINE-1-PHOSPHATE TRANSFERASE; TRANSLATIONAL REGULATION; GLUCOSE-HOMEOSTASIS; TRIAZINE LIBRARY; CELL-SURVIVAL; MEMBRANE; KINASE
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/50153
- DOI
- 10.1016/j.cmet.2005.11.005
- ISSN
- 1550-4131
- Article Type
- Article
- Citation
- CELL METABOLISM, vol. 2, no. 6, page. 361 - 371, 2005-12
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