FoxO suppresses endoplasmic reticulum stress to inhibit growth of Tsc1-deficient tissues under nutrient restriction.

Avantika Gupta,Hugo Stocker

doi:10.7554/elife.53159

Abstract

The transcription factor FoxO has been shown to block proliferation and progression in mTORC1-driven tumorigenesis but the picture of the relevant FoxO target genes remains incomplete. Here, we employed RNA-seq profiling on single clones isolated using laser capture microdissection from Drosophila larval eye imaginal discs to identify FoxO targets that restrict the proliferation of Tsc1-deficient cells under nutrient restriction (NR). Transcriptomics analysis revealed downregulation of endoplasmic reticulum-associated protein degradation pathway components upon foxo knockdown. Induction of ER stress pharmacologically or by suppression of other ER stress response pathway components led to an enhanced overgrowth of Tsc1 knockdown tissue. Increase of ER stress in Tsc1 loss-of-function cells upon foxo knockdown was also confirmed by elevated expression levels of known ER stress markers. These results highlight the role of FoxO in limiting ER stress to regulate Tsc1 mutant overgrowth.

Highlights

The phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin complex 1 network is the central regulator of cell growth, survival, and metabolism (Manning and Toker, 2017; Saxton and Sabatini, 2017). mTORC1 integrates growth factor signaling via Akt with the intracellular nutrient and energy status to promote anabolism and suppress catabolic processes (BenSahra and Manning, 2017)
Evaluating the nuclear Forkhead box O (FoxO) antibody staining in Tsc1 mutant cells (Manning et al, 2005) in time-course experiments revealed that a 12 hr shift was sufficient to achieve an adequate foxo knockdown (Figure 1B and B’)
The transcription factor FoxO has a distinct activity in different biological contexts

Summary

Introduction

The phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin complex 1 (mTORC1) network is the central regulator of cell growth, survival, and metabolism (Manning and Toker, 2017; Saxton and Sabatini, 2017). mTORC1 integrates growth factor signaling via Akt with the intracellular nutrient and energy status to promote anabolism and suppress catabolic processes (BenSahra and Manning, 2017). The TSC complex inactivates mTORC1 downstream of Akt (Potter et al, 2002) via its GTPase activating protein (GAP) activity towards Rheb (Saucedo et al, 2003; Stocker et al, 2003; Zhang et al, 2003) Another major downstream target of Akt is the transcription factor Forkhead box O (FoxO) (Junger et al, 2003). The role of FoxO as a bona fide tumor suppressor is not established since it can function as tumor-promoting depending on the biological context (van Doeselaar and Burgering, 2018) This underscores the importance of understanding the regulation of FoxO and the downstream signaling in a particular context of interest (Brown and Webb, 2018)

Methods

Results

Conclusion