A functional genetic screen defines the AKT-induced senescence signaling network

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Chan , K T , Blake , S , Zhu , H , Kang , J , Trigos , A S , Madhamshettiwar , P B , Diesch , J , Paavolainen , L , Horvath , P , Hannan , R D , George , A J , Sanij , E , Hannan , K M , Simpson , K J & Pearson , R B 2020 , ' A functional genetic screen defines the AKT-induced senescence signaling network ' , Cell Death and Differentiation , vol. 27 , no. 2 , pp. 725-741 . https://doi.org/10.1038/s41418-019-0384-8

Title: A functional genetic screen defines the AKT-induced senescence signaling network
Author: Chan, Keefe T.; Blake, Shaun; Zhu, Haoran; Kang, Jian; Trigos, Anna S.; Madhamshettiwar, Piyush B.; Diesch, Jeannine; Paavolainen, Lassi; Horvath, Peter; Hannan, Ross D.; George, Amee J.; Sanij, Elaine; Hannan, Katherine M.; Simpson, Kaylene J.; Pearson, Richard B.
Contributor organization: Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Date: 2020-02
Language: eng
Number of pages: 17
Belongs to series: Cell Death and Differentiation
ISSN: 1350-9047
DOI: https://doi.org/10.1038/s41418-019-0384-8
URI: http://hdl.handle.net/10138/313124
Abstract: Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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