biostudies-literatureChan KTCancer Council VictoriaCancer Foundation Finland srDepartment of Health | National Health and Medical Research Council725-741https://www.ebi.ac.uk/biostudies/studies/S-EPMC7205866biostudies-literatureUnknown27(2)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 proCell death and differentiationA functional genetic screen defines the AKT-induced senescence signaling network.PMC7205866APP1053792APP1065118190113Hannan KMSimpson KJZhu HBlake SHorvath PSanij EPaavolainen LGeorge AJTrigos ASHannan RDPearson RBMadhamshettiwar PBChan KTDiesch JKang JfalseA functional genetic screen defines the AKT-induced senescence signaling network.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 pro2020-01-01T00:00:00Z2020 Feb2026-04-14T13:26:56.799Z2025-05-29T22:00:51.363ZS-EPMC72058663128554510.1038/s41418-019-0384-8