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

Chan, Keefe; Blake, Shaun; Zhu, Haoran; Kang, Jian; Trigos, Anna S.; Madhamshettiwar, Piyush; Diesch, Jeannine; Paavolainen, Lassi; Horvath, Peter; Hannan, Ross; George, Amee; Sanij, Elaine; Hannan, Kate; Simpson, Kaylene J.; Pearson, Richard B

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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)...[Show more]

dc.contributor.authorChan, Keefe
dc.contributor.authorBlake, Shaun
dc.contributor.authorZhu, Haoran
dc.contributor.authorKang, Jian
dc.contributor.authorTrigos, Anna S.
dc.contributor.authorMadhamshettiwar, Piyush
dc.contributor.authorDiesch, Jeannine
dc.contributor.authorPaavolainen, Lassi
dc.contributor.authorHorvath, Peter
dc.contributor.authorHannan, Ross
dc.contributor.authorGeorge, Amee
dc.contributor.authorSanij, Elaine
dc.contributor.authorHannan, Kate
dc.contributor.authorSimpson, Kaylene J.
dc.contributor.authorPearson, Richard B
dc.date.accessioned2020-09-23T01:34:40Z
dc.date.available2020-09-23T01:34:40Z
dc.identifier.issn1350-9047
dc.identifier.urihttp://hdl.handle.net/1885/211369
dc.description.abstractExquisite 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
dc.description.sponsorshipCancer Council Victoria and National Health and Medical Research Council (NHMRC) Grants, and an NHMRC Senior Research Fellowship to RBP supported this work. The LENDULET-BIOMAG Grant (2018- 342) and European Regional Development Funds (GINOP-2.3.2-15- 2016-00006, GINOP-2.3.2-15-2016-00037) supported PH. The Australian Cancer Research Foundation, the Australian Phenomics Network through the Australian Government’s National Collaborative Research Infrastructure Strategy program and the PMCC Foundation fund the VCFG (KJS).
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherSpringer Nature
dc.rights© The Author(s) 2019.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceCell Death and Differentiation
dc.titleA functional genetic screen defines the AKT-induced senescence signaling network
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume27
dc.date.issued2020
local.identifier.absfor111201 - Cancer Cell Biology
local.identifier.absfor060103 - Cell Development, Proliferation and Death
local.identifier.ariespublicationu6269649xPUB633
local.publisher.urlhttp://www.nature.com/cdd/
local.type.statusPublished Version
local.contributor.affiliationChan, Keefe, Peter MacCallum Cancer Centre
local.contributor.affiliationBlake, Shaun, Peter MacCallum Cancer Centre
local.contributor.affiliationZhu, Haoran, Peter MacCallum Cancer Centre
local.contributor.affiliationKang, Jian, Peter MacCalllum Cancer Centre
local.contributor.affiliationTrigos, Anna S., Peter MacCallum Cancer Centre
local.contributor.affiliationMadhamshettiwar, Piyush, Peter MacCallum Cancer Centre
local.contributor.affiliationDiesch, Jeannine, Josep Carreras Leukaemia Research Institute
local.contributor.affiliationPaavolainen, Lassi, University of Helsinki
local.contributor.affiliationHorvath, Peter, Hungarian Academy of Sciences
local.contributor.affiliationHannan, Ross, College of Health and Medicine, ANU
local.contributor.affiliationGeorge, Amee, College of Health and Medicine, ANU
local.contributor.affiliationSanij, Elaine, Peter MacCallum Cancer Centre
local.contributor.affiliationHannan, Kate, College of Health and Medicine, ANU
local.contributor.affiliationSimpson, Kaylene J., Peter MacCallum Cancer Centre
local.contributor.affiliationPearson, Richard B, Peter MacCallum Cancer Centre
local.bibliographicCitation.startpage725
local.bibliographicCitation.lastpage741
local.identifier.doi10.1038/s41418-019-0384-8
local.identifier.absseo920102 - Cancer and Related Disorders
dc.date.updated2020-06-23T00:57:53Z
local.identifier.scopusID2-s2.0-85068693871
dcterms.accessRightsOpen Access
dc.provenance© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
dc.rights.licenseCreative Commons Attribution 4.0 International License
CollectionsANU Research Publications

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