Identification of Modulators of TRAIL-Induced Apoptosis via RNAi-Based Phenotypic Screening

New opportunities in mammalian functional genomics are emerging through the combination of high throughput technology and methods that allow manipulation of gene expression in living cells. Here we describe the application of an RNAi-based forward genomics approach toward understanding the biology a...

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Bibliographic Details
Published in:Molecular cell 2003-09, Vol.12 (3), p.627-637
Main Authors: Aza-Blanc, Pedro, Cooper, Christopher L., Wagner, Klaus, Batalov, Serge, Deveraux, Quinn L., Cooke, Michael P.
Format: Article
Language:English
Subjects:
Apoptosis - genetics
Apoptosis - immunology
Apoptosis Regulatory Proteins
Gene Expression Regulation - genetics
Genetic Testing - methods
HeLa Cells
Humans
Immunologic Surveillance - immunology
Membrane Glycoproteins - immunology
Mitochondria - genetics
Mitochondria - metabolism
Neoplasms - immunology
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-myc - metabolism
RNA Interference - immunology
Signal Transduction - genetics
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha - immunology
Wnt Proteins
Zebrafish Proteins
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Summary:New opportunities in mammalian functional genomics are emerging through the combination of high throughput technology and methods that allow manipulation of gene expression in living cells. Here we describe the application of an RNAi-based forward genomics approach toward understanding the biology and mechanism of TRAIL-induced apoptosis. TRAIL is a TNF superfamily member that induces selective cytotoxicity of tumor cells when bound to its cognate receptors. In addition to detecting well-characterized genes in the apoptosis pathway, we uncover several modulators including DOBI, a gene required for progression of the apoptotic signal through the intrinsic mitochondrial cell death pathway, and MIRSA, a gene that acts to limit TRAIL-induced apoptosis. Moreover, our data suggest a role for MYC and the WNT pathway in maintaining susceptibility to TRAIL. Collectively, these observations offer several insights on how TRAIL mediates the selective killing of tumor cells and demonstrate the utility of large-scale RNAi screens in mammalian cells.
ISSN:1097-2765
1097-4164
DOI:10.1016/S1097-2765(03)00348-4