title: The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Beatrice T
authors.initials: BT
authors.lastname: Wang
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ducker
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Barczak
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barbeau
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis*; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus