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Genome-wide shRNA screen reveals increased mitochondrial dependence upon mTORC2 addiction

Colombi, M. and Molle, K. D. and Benjamin, D. and Rattenbacher-Kiser, K. and Schaefer, C. and Betz, C. and Thiemeyer, A. and Regenass, U. and Hall, M. N. and Moroni, C.. (2011) Genome-wide shRNA screen reveals increased mitochondrial dependence upon mTORC2 addiction. Oncogene, 30 (13). pp. 1551-1565.

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Abstract

Release from growth factor dependence and acquisition of signalling pathway addiction are critical steps in oncogenesis. To identify genes required on mammalian target of rapamycin (mTOR) addiction, we performed a genome-wide short hairpin RNA screen on a v-H-ras-transformed Pten-deficient cell line that displayed two alternative growth modes, interleukin (IL)-3-independent/mTOR-addicted proliferation (transformed growth mode) and IL-3-dependent/mTOR-non-addicted proliferation (normal growth mode). We screened for genes required only in the absence of IL-3 and thus specifically for the transformed growth mode. The top 800 hits from this conditional lethal screen were analyzed in silico and 235 hits were subsequently rescreened in two additional Pten-deficient cell lines to generate a core set of 47 genes. Hits included genes encoding mTOR and the mTOR complex 2 (mTORC2) component rictor and several genes encoding mitochondrial functions including components of the respiratory chain, adenosine triphosphate synthase, the mitochondrial ribosome and mitochondrial fission factor. Small interfering RNA knockdown against a sizeable fraction of these genes triggered apoptosis in human cancer cell lines but not in normal fibroblasts. We conclude that mTORC2-addicted cells require mitochondrial functions that may be novel drug targets in human cancer.Oncogene advance online publication, 20 December 2010; doi:10.1038/onc.2010.539.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Growth and Development (Moroni)
03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Growth and Development (Moroni)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Moroni, Christoph and Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Macmillan
ISSN:0950-9232
e-ISSN:1476-5594
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:29 Aug 2018 16:07
Deposited On:08 Jun 2012 06:51

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