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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\u2013dependent 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.<\/jats:p>","DOI":"10.1073\/pnas.1103746108","type":"journal-article","created":{"date-parts":[[2011,8,29]],"date-time":"2011-08-29T22:04:21Z","timestamp":1314655461000},"page":"15201-15206","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":115,"title":["The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile"],"prefix":"10.1073","volume":"108","author":[{"given":"Beatrice T.","family":"Wang","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Ducker","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Berkeley, CA 94720; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J.","family":"Barczak","sequence":"additional","affiliation":[{"name":"Lung Biology Center, University of California, San Francisco, CA 4158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Barbeau","sequence":"additional","affiliation":[{"name":"Lung Biology Center, University of California, San Francisco, CA 4158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Erle","sequence":"additional","affiliation":[{"name":"Lung Biology Center, University of California, San Francisco, CA 4158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevan M.","family":"Shokat","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158;"},{"name":"Department of Chemistry, University of California, Berkeley, CA 94720; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0092-8674(00)00117-3","article-title":"TOR, a central controller of cell growth","volume":"103","author":"Schmelzle T","year":"2000","unstructured":"T Schmelzle, MN Hall, TOR, a central controller of cell growth. 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