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

Keefe T. Chan, Shaun Blake, Haoran Zhu, Jian Kang, Anna S. Trigos, Piyush B. Madhamshettiwar, Jeannine Diesch, Lassi Paavolainen, P. Horváth, Ross D. Hannan, Amee J. George, Elaine Sanij, Katherine M. Hannan, Kaylene J. Simpson, Richard B. Pearson

Research output: Article

2 Citations (Scopus)

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.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusPublished - jan. 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Chan, K. T., Blake, S., Zhu, H., Kang, J., Trigos, A. S., Madhamshettiwar, P. B., Diesch, J., Paavolainen, L., Horváth, P., Hannan, R. D., George, A. J., Sanij, E., Hannan, K. M., Simpson, K. J., & Pearson, R. B. (2019). A functional genetic screen defines the AKT-induced senescence signaling network. Cell Death and Differentiation. https://doi.org/10.1038/s41418-019-0384-8