期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 37, 页码 15201-15206出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103746108
关键词
sterol regulatory element-binding protein-2; eIF4E-binding protein-1 phosphorylation; 3-hydroxy-3-methylglutaryl-CoA reductase; thioredoxin interacting protein; expression array
资金
- University of California Cancer Research Coordinating Committee
- Samuel Waxman Cancer Research Foundation
- Accelerate Brain Cancer, Multiple Myeloma Translational Institute
- Sandler Asthma Basic Research Center Functional Genomics Core Facility
- National Institutes of Health/National Center for Research Resources (University of California, San Francisco, Clinical and Translational Science Institute) [UL1 RR024131]
- Multiple Myeloma Translational Institute
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin inhibits only a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. A number of studies have highlighted mTORC1 as a regulator of lipid homeostasis. We show that the ATP-competitive inhibitor PP242, but not rapamycin, significantly down-regulates cholesterol biosynthesis genes in a 4E-BP1-dependent manner in NIH 3T3 cells, whereas S6 kinase 1 is the dominant regulator in hepatocellular carcinoma cells. To identify other rapamycin-resistant transcriptional outputs of mTOR, we compared the expression profiles of NIH 3T3 cells treated with rapamycin versus PP242. PP242 caused 1,666 genes to be differentially expressed whereas rapamycin affected only 88 genes. Our analysis provides a genomewide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.
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