A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications
Program in Gene Function and Expression; Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Pathology; Department of Neurology; Department of Surgery
Medical Subject Headings
Activating Transcription Factors; inhibitors; Animals; Apoptosis; Benzenesulfonates; Brain Neoplasms; Cyclic AMP Response Element-Binding Protein; *Gene Expression Profiling; Glioma; Humans; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Proto-Oncogene Proteins c-bcl-2; Pyridines; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Cells, Cultured
Genetics and Genomics
Activating transcription factor-5 (ATF5) is highly expressed in malignant glioma and has a key role in promoting cell survival. Here we perform a genome-wide RNAi screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS-mitogen-activated protein kinase or phosphoinositide-3-kinase signaling cascade leads to induction of the transcription factor cAMP response element-binding protein-3-like-2 (CREB3L2), which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF kinase inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse models. Our results demonstrate that ATF5 is essential in malignant glioma genesis and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.
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Citation: Nat Med. 2010 Jun;16(6):671-7. Epub 2010 May 23. Link to article on publisher's site